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1.  Enhanced Inducible Costimulator Ligand (ICOS-L) Expression on Dendritic Cells in Interleukin-10 Deficiency and Its Impact on T-Cell Subsets in Respiratory Tract Infection 
Molecular Medicine  2013;19(1):346-356.
An association between inducible costimulator ligand (ICOS-L) expression and interleukin (IL)-10 production by dendritic cells (DCs) has been commonly found in infectious disease. DCs with higher ICOS-L expression and IL-10 production are reportedly more efficient in inducing regulatory T cells (Tregs). Here we use the Chlamydia muridarum (Cm) lung infection model in IL-10 knockout (KO) mice to test the relationship between IL-10 production and ICOS-L expression by DCs. We examined ICOS-L expression, the development of T-cell subsets, including Treg, Th17 and Th1 cell, in the background of IL-10 deficiency and its relationship with ICOS-L/ICOS signaling after infection. Surprisingly, we found that the IL-10 KO mice exhibited significantly higher ICOS-L expression by DCs. Moreover, IL-10 KO mice showed lower Tregs but higher Th17 and Th1 responses, but only the Th17 response depended on ICOS signaling. Consistently, most of the Th17 cells were ICOS+, whereas most of the Th1 cells were ICOS− in the infected mice. Furthermore, neutralization of IL-17 in IL-10 KO mice significantly exacerbated lung infection. The data suggest that ICOS-L expression on DC may be negatively regulated by IL-10 and that ICOS-L expression on DC in the presence or absence of IL-10 costimulation may promote Treg or Th17 response, without significant impact on Th1.
doi:10.2119/molmed.2013.00035
PMCID: PMC3883961  PMID: 24100657
2.  Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function 
The Journal of Experimental Medicine  2002;195(8):1033-1041.
Interaction between inducible costimulator (ICOS) and its ligand is implicated in the induction of cell-mediated and humoral immune responses. However, the molecular details of this interaction are unknown. We report here a mutagenesis analysis of residues in ICOS that are critical for ligand binding. A three-dimensional model of the extracellular immunoglobulin-like domain of ICOS was used to map the residues conserved within the CD28 family. This analysis identified a surface patch containing the characteristic “PPP” sequence and is conserved in human and mouse ICOS. Mutations in this region of human ICOS reduce or abolish ligand binding. Our results suggest that the ligand binding site in ICOS maps to a region overlapping yet distinct from the CD80/CD86 binding sites in CD28 and cytotoxic T lymphocyte antigen (CTLA)-4. Thus, the analysis suggests that differences in ligand binding specificity between these related costimulatory molecules have evolved by utilization of overlapping regions with different patterns of conserved and nonconserved residues. Two site-specific mutants generated in the course of our studies bound ICOS ligand with higher avidity than wild-type ICOS. An S76E mutant protein of ICOS blocked T cell costimulatory function of ICOS ligand and inhibited T cell response to allogeneic antigens superior to wild-type ICOS. Our studies thus identified critical residues involving in ICOS receptor–ligand interaction and provide new modulators for immune responses.
doi:10.1084/jem.20011607
PMCID: PMC2193694  PMID: 11956294
ICOS; CD28; molecular model; mutagenesis; avidity
3.  The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity 
Journal of Clinical Investigation  2003;112(2):234-243.
Inducible costimulatory molecule (ICOS) plays a pivotal role in T cell activation and Th1/Th2 differentiation. ICOS blockade has disparate effects on immune responses depending on the timing of blockade. Its role in transplantation immunity, however, remains incompletely defined. We used a vascularized mouse cardiac allograft model to explore the role of ICOS signaling at different time points after transplantation, targeting immune initiation (early blockade) or the immune effector phase (delayed blockade). In major histocompatibility–mismatched recipients, ICOS blockade prolonged allograft survival using both protocols but did so more effectively in the delayed-treatment group. By contrast, in minor histocompatibility–mismatched recipients, early blockade accelerated rejection and delayed blockade prolonged graft survival. Alloreactive CD4+ T cell expansion and alloantibody production were suppressed in both treatment groups, whereas only delayed blockade resulted in suppression of effector CD8+ T cell generation. After delayed ICOS blockade, there was a diminished frequency of allospecific IL-10–producing cells and an increased frequency of both IFN-γ– and IL-4–producing cells. The beneficial effects of ICOS blockade in regulating allograft rejection were seen in the absence of CD28 costimulation but required CD8+ cells, cytotoxic T lymphocyte antigen-4, and an intact signal transducer and activator of transcription–6 pathway. These data define the complex functions of the ICOS-B7h pathway in regulating alloimmune responses in vivo.
doi:10.1172/JCI200317008
PMCID: PMC164288  PMID: 12865411
4.  Anti-Chlamydial Th17 Responses Are Controlled by the Inducible Costimulator Partially through Phosphoinositide 3-Kinase Signaling 
PLoS ONE  2012;7(12):e52657.
We previously showed that mice deficient in the Inducible Costimulator ligand (ICOSL-KO) develop more severe disease and lung pathology with delayed bacterial clearance upon respiratory infection of Chlamydia muridarum. Importantly, the exacerbation of disease in ICOSL-KO mice was seen despite heightened IFN-γ/Th1 responses, the major defense mechanisms against Chlamydia. To gain insight into the mechanism of ICOS function in this model, we presently analyzed anti-Chlamydia immune responses in mice lacking the entire ICOS (ICOS-KO) versus knock-in mice expressing a mutant ICOS (ICOS-Y181F) that has selectively lost the ability to activate phosphoinositide 3-kinase (PI3K). Like ICOSL-KO mice, ICOS-KO mice showed worse disease with elevated IFN-γ/Th1 responses compared to wild-type (WT) mice. ICOS-Y181F mice developed much milder disease compared to ICOS-KO mice, yet they were still not fully protected to the WT level. This partial protection in ICOS-Y181F mice could not be explained by the magnitude of IFN-γ/Th1 responses since these mice developed a similar level of IFN-γ response compared to WT mice. It was rather IL-17/Th17 responses that reflected disease severity: IL-17/Th17 response was partially impaired in ICOS-Y181F mice compared to WT, but was substantially stronger than that of ICOS-KO mice. Consistently, we found that both polarization and expansion of Th17 cells were partially impaired in ICOS-Y181F CD4 T cells, and was further reduced in ICOS-KO CD4 T cells in vitro. Our results indicate that once the IFN-γ/Th1 response is above a threshold level, the IL-17/Th17 response becomes a limiting factor in controlling Chlamydia lung infection, and that ICOS plays an important role in promoting Th17 responses in part through the activation of PI3K.
doi:10.1371/journal.pone.0052657
PMCID: PMC3527575  PMID: 23285133
5.  Inducible Costimulator Controls Migration of T Cells to the Lungs via Down-Regulation of CCR7 and CD62L 
We and others reported that Inducible costimulator-deficient (ICOS−/−) mice manifest a defect in Th2-mediated airway inflammation, which was attributed to reduced Th2 differentiation in the absence of ICOS signaling. Interestingly, the number of CD4 T cells present in the airways and lungs after sensitization and challenge is significantly reduced in ICOS−/− mice. We now show that this reduction is not attributable simply to a reduced proliferation of ICOS−/− cells, because significantly more ICOS−/− than wild-type activated CD4 T cells are present in the lymph nodes, suggesting that more ICOS−/− CD4 T cells than wild-type CD4 T cells migrated into the lymph nodes. Further investigation revealed that activated ICOS−/− CD4 T cells express higher concentrations of the lymph node homing receptors, CCR7 and CD62L, than do wild-type CD4 T cells, leading to a preferential return of ICOS−/− cells to the nondraining lymph nodes rather than the lungs. Blocking reentry into the lymph nodes after the initiation of Th2-mediated airway inflammation equalized the levels of CD4 and granulocyte infiltration in the lungs of wild-type and ICOS−/− mice. Our results demonstrate that in wild-type CD4 T cells, co-stimulation with ICOS promotes the down-regulation of CCR7 and CD62L after activation, leading to a reduced return of activated CD4 T cells to the lymph nodes and a more efficient entry into the lungs.
doi:10.1165/rcmb.2010-0466OC
PMCID: PMC3208611  PMID: 21421907
ICOS; co-stimulation; Th2; airway inflammation; T-cell migration
6.  Role of CD28, CTLA4 and ICOS costimulation in Acute Graft-versus-Host Disease in Mice 
T cells deficient for CD28 have reduced ability to expand and survive, but still cause graft-versus-host disease (GVHD). Inducible costimulator (ICOS), the third member of the CD28 family, is expressed on antigen-activated T cells and has unique roles in T-cell activation and effector function. We hypothesized that ICOS contributes to the development of GVHD in the absence of B7:CD28/CTLA4 costimulation. In this study, we evaluated the roles of CD28, CTLA4 and ICOS in the pathogenesis of acute GVHD under myeloablative allogeneic bone marrow transplantation (BMT). Unexpectedly, we found that blocking CD28 and CTLA4 signals using the clinically relevant reagent, CTLA4-Ig, results in the enhancement of GVHD severity mediated by CD4+ T cells, and such treatment does not add any benefit to blockade of ICOS. In contrast, selectively blocking CD28 and ICOS but not CTLA4 prevents GVHD more effectively than blocking either CD28 or ICOS alone. Taken together, these results indicate that CD28 and ICOS are synergistic in promoting GVHD, whereas the CTLA4-signal is required for T-cell tolerance regardless of ICOS signaling. Thus, blocking CD28 and ICOS while sparing CTLA4 represents a promising approach for abrogating pathogenic T-cell responses after allogeneic BMT.
doi:10.1016/j.bbmt.2011.01.018
PMCID: PMC3131782  PMID: 21447398
7.  Inducible Costimulator Expression Regulates the Magnitude of Th2-Mediated Airway Inflammation by Regulating the Number of Th2 Cells 
PLoS ONE  2009;4(11):e7525.
Background
Inducible Costimulator (ICOS) is an important regulator of Th2 lymphocyte function and a potential immunotherapeutic target for allergy and asthma. A SNP in the ICOS 5′ promoter in humans is associated with increased atopy and serum IgE in a founder population and increased ICOS surface expression and Th2 cytokine production from peripheral blood mononuclear cells. However, it is unknown if increased ICOS expression contributes to disease progression or is a result of disease pathology.
Methodology/Principal Findings
We developed a mouse model in which ICOS surface expression levels are genetically predetermined to test our hypothesis that genetic regulation of ICOS expression controls the severity of Th2 responses in vivo. Using ICOS+/+ and ICOS+/− mice in a Th2 model of airway inflammation, we found that T cells from the ICOS+/− mice had reduced ICOS expression and decreased Th2-mediated inflammation in vivo. Although the activation status of the T cells did not differ, T cells isolated from the lungs and draining lymph nodes of ICOS+/− mice at the peak of inflammation produced less Th2 cytokines upon stimulation ex vivo. Using 4get mice, which express GFP upon IL-4 transcription, we determined that the decreased Th2 cytokines in ICOS+/− is due to reduced percentage of Th2 cells and not a defect in their ability to produce IL-4.
Conclusion
These data suggest that in both mice and humans, the level of ICOS surface expression regulates the magnitude of the in vivo Th2 response, perhaps by influencing Th2 differentiation.
doi:10.1371/journal.pone.0007525
PMCID: PMC2768787  PMID: 19888475
8.  Inducible co-stimulator (ICOS) up-regulation on activated T-cells in chronic graft-vs.-host disease following dog-leukocyte-antigen-nonidentical hematopoietic cell transplantation: A potential therapeutic target 
Transplantation  2013;96(1):34-41.
Background
Inducible co-stimulator (ICOS), a member of the CD28 family of costimulatory molecules, is induced on CD4+ and CD8+ T-cells following their activation. ICOS functions as an essential immune regulator and ICOS blockade is a potential approach to immune modulation in allogeneic transplantation. Here, we describe the expression profile of ICOS in dogs and determine whether ICOS expression is up-regulated during chronic graft versus host disease (GVHD) and host versus graft (HVG) reactions in the canine hematopoietic cell transplantation model.
Methods
Monoclonal antibodies against cell surface-expressed ICOS were produced and tested in vitro for suppression of canine mixed leukocyte reactions (MLR). Expression of ICOS on CD3+ cells was evaluated by flow cytometry using peripheral blood, lymph nodes and splenocytes obtained from dogs undergoing GVH and HVG reactions.
Results
Canine ICOS was expressed in an inducible pattern on T-cells activated by Con A, anti-CD3 mAb in combination with anti-CD28 mAb, and alloantigen stimulation. Immunosuppressive effects of ICOS blockade were observed in MLR using peripheral blood mononuclear cells from dog-leukocyte-antigen-nonidentical dogs. Immunosuppressive effects of ICOS blockade were observed in MLR when anti-ICOS was combined with suboptimal concentrations of cytotoxic T-lymphocyte antigen 4-Ig (CTLA4-Ig) or cyclosporine. ICOS expression was significantly up-regulated on T-cells in dogs undergoing graft rejection or chronic GVHD after allogeneic hematopoietic cell transplantation.
Conclusion
These studies suggest that ICOS plays a role in graft rejection and GVHD in an out-bred animal model, and ICOS blockade may be an approach to prevention and treatment of chronic GVHD.
doi:10.1097/TP.0b013e318295c025
PMCID: PMC3696413  PMID: 23694952
dog; hematopoietic cell transplantation; ICOS; graft-versus-host disease; costimulatory molecule
9.  B7RP-1-ICOS Interactions Are Required for Optimal Infection-Induced Expansion of CD4+ Th1 and Th2 Responses1 
Although initial reports linked the costimulatory molecule ICOS preferentially with the deelopment of Th2 cells, there is evidence that it is not required for protective type 2 immunity to helminths and that it contributes to Th1 and Th2 responses to other parasites. To address the role of ICOS in the development of infection-induced polarized Th cells, ICOS-/- mice were infected with Trichuris muris or Toxoplasma gondii. Wild-type mice challenged with T. muris developed Th2 responses and expelled these helminths by day 18 postinfection, whereas ICOS-/- mice failed to clear worms and produced reduced levels of type 2 cytokines. However, by day 35 postinfection, ICOS-/- mice were able to mount an effective Th2 response and worms were expelled. This delay in protective immunity was associated with a defect in infection-induced increases in the number of activated and proliferating CD4+ T cells. Similarly, following challenge with T. gondii ICOS was required for optimal proliferation by CD4+ T cells. However, the reduced number of activated CD4+ T cells and associated defect in the production of IFN-γ did not result in increased susceptibility to T. gondii, but rather resulted in decreased CNS pathology during the chronic phase of this infection. Taken together, these data are consistent with a model in which ICOS is not involved in dictating polarity of the Th response but rather regulates the expansion of these subsets.
PMCID: PMC1780268  PMID: 16887998
10.  Protective Effector Memory CD4 T Cells Depend on ICOS for Survival 
PLoS ONE  2011;6(2):e16529.
Memory CD4 T cells play a vital role in protection against re-infection by pathogens as diverse as helminthes or influenza viruses. Inducible costimulator (ICOS) is highly expressed on memory CD4 T cells and has been shown to augment proliferation and survival of activated CD4 T cells. However, the role of ICOS costimulation on the development and maintenance of memory CD4 T cells remains controversial. Herein, we describe a significant defect in the number of effector memory (EM) phenotype cells in ICOS−/− and ICOSL−/− mice that becomes progressively more dramatic as the mice age. This decrease was not due to a defect in the homeostatic proliferation of EM phenotype CD4 T cells in ICOS−/− or ICOSL−/− mice. To determine whether ICOS regulated the development or survival of EM CD4 T cells, we utilized an adoptive transfer model. We found no defect in development of EM CD4 T cells, but long-term survival of ICOS−/− EM CD4 T cells was significantly compromised compared to wild-type cells. The defect in survival was specific to EM cells as the central memory (CM) ICOS−/− CD4 T cells persisted as well as wild type cells. To determine the physiological consequences of a specific defect in EM CD4 T cells, wild-type and ICOS−/− mice were infected with influenza virus. ICOS−/− mice developed significantly fewer influenza-specific EM CD4 T cells and were more susceptible to re-infection than wild-type mice. Collectively, our findings demonstrate a role for ICOS costimulation in the maintenance of EM but not CM CD4 T cells.
doi:10.1371/journal.pone.0016529
PMCID: PMC3041765  PMID: 21364749
11.  ICOS Costimulation Expands Th2 Immunity by Augmenting Migration of Lymphocytes to Draining Lymph Nodes1 
The T cell costimulatory molecule ICOS regulates Th2 effector function in allergic airway disease. Recently, several studies with ICOS−/− mice have also demonstrated a role for ICOS in Th2 differentiation. To determine the effects of ICOS on the early immune response, we investigated augmenting ICOS costimulation in a Th2-mediated immune response to Schistosoma mansoni antigens. We found that augmenting ICOS costimulation with B7RP-1-Fc increased the accumulation of T and B cells in the draining lymph nodes post-immunization. Interestingly, the increased numbers were due in part to increased migration of undivided antigen-specific TCR transgenic T cells and surprisingly B cells, as well as non-TCR transgenic T cells. B7RP-1-Fc also increased the levels of the chemokines, CCL21 and CXCL13, in the draining lymph node, suggesting ICOS costimulation contributes to migration by direct or indirect effects on, dendritic cells, stromal cells and high endothelial venules. Further, the effects of B7RP-1-Fc were not dependent on immunization. Our data support a model in which ICOS costimulation augments the pool of lymphocytes in the draining lymph nodes leading to an increase in the frequency of potentially reactive T and B cells.
PMCID: PMC2560985  PMID: 18606653
Costimulation; Th1/Th2 cells; B cells; Rodent; Spleen and Lymph Nodes
12.  Plasmacytoid dendritic cells prime IL-10–producing T regulatory cells by inducible costimulator ligand 
Although there is evidence for distinct roles of myeloid dendritic cells (DCs [mDCs]) and plasmacytoid pre-DCs (pDCs) in regulating T cell–mediated adaptive immunity, the concept of functional DC subsets has been questioned because of the lack of a molecular mechanism to explain these differences. In this study, we provide direct evidence that maturing mDCs and pDCs express different sets of molecules for T cell priming. Although both maturing mDCs and pDCs upregulate the expression of CD80 and CD86, only pDCs upregulate the expression of inducible costimulator ligand (ICOS-L) and maintain high expression levels upon differentiation into mature DCs. High ICOS-L expression endows maturing pDCs with the ability to induce the differentiation of naive CD4 T cells to produce interleukin-10 (IL-10) but not the T helper (Th)2 cytokines IL-4, -5, and -13. These IL-10–producing T cells are T regulatory cells, and their generation by ICOS-L is independent of pDC-driven Th1 and Th2 differentiation, although, in the later condition, some contribution from endogenous IL-4 cannot be completely ruled out. Thus, in contrast to mDCs, pDCs are poised to express ICOS-L upon maturation, which leads to the generation of IL-10–producing T regulatory cells. Our findings demonstrate that mDC and pDCs are intrinsically different in the expression of costimulatory molecules that drive distinct types of T cell responses.
doi:10.1084/jem.20061660
PMCID: PMC2118437  PMID: 17200410
13.  Role for Inducible Costimulator in Control of Salmonella enterica Serovar Typhimurium Infection in Mice  
Infection and Immunity  2006;74(2):1050-1061.
Inducible costimulator (ICOS) is expressed on activated T cells and plays a key role in sustaining and enhancing the effector function of CD4 T cells. Given the function of this molecule in sustaining T-cell responses, we reasoned that ICOS might play an important role in a prolonged infection model, such as Salmonella infection of mice. To test this hypothesis, wild-type (WT) and ICOS-deficient (ICOS−/−) mice were infected systemically with a Salmonella enterica serovar Typhimurium strain expressing the chicken ovalbumin gene (Salmonella-OVA). ICOS−/− mice exhibited greater splenomegaly than WT mice and showed delayed bacterial clearance. The acquired immune response in this model was slow to develop. Maximal T-cell responses to Salmonella-OVA were detected at 3 weeks postinfection in both WT and ICOS−/− mice. CD4 T-cell-dependent gamma interferon production and a class switch to immunoglobulin G2a were severely reduced in ICOS−/− mice. ICOS−/− mice also exhibited a substantial defect in antigen-specific CD8 T-cell responses. In vitro, the effect of anti-ICOS on CD8 T-cell division was greater when CD8 T cells rather than CD4 T cells expressed ICOS, suggesting that the in vivo effects of ICOS on CD8 T cells could be direct. Taken together, these studies show that ICOS plays a critical role in control of Salmonella infection in mice, with effects on antibody, Th1, and CD8 T-cell responses.
doi:10.1128/IAI.74.2.1050-1061.2006
PMCID: PMC1360312  PMID: 16428752
14.  Single and Coexpression of CXCR4 and CXCR5 Identifies CD4 T Helper Cells in Distinct Lymph Node Niches during Influenza Virus Infection 
Journal of Virology  2012;86(13):7146-7157.
Influenza virus infection results in strong, mainly T-dependent, extrafollicular and germinal center B cell responses, which provide lifelong humoral immunity against the homotypic virus strain. Follicular T helper cells (TFH) are key regulators of humoral immunity. Questions remain regarding the presence, identity, and function of TFH subsets regulating early extrafollicular and later germinal center B cell responses. This study demonstrates that ICOS but not CXCR5 marks T cells with B helper activity induced by influenza virus infection and identifies germinal center T cells (TGC) as lymph node-resident CD4+ ICOS+ CXCR4+ CXCR5+ PSGL-1lo PD-1hi cells. The CXCR4 expression intensity further distinguished their germinal center light and dark zone locations. This population emerged strongly in regional lymph nodes and with kinetics similar to those of germinal center B cells and were the only TFH subsets missing in influenza virus-infected, germinal center-deficient SAP−/− mice, mice which were shown previously to lack protective memory responses after a secondary influenza virus challenge, thus indicting the nonredundant functions of CXCR4- and CXCR5-coexpressing CD4 helper cells in antiviral B cell immunity. CXCR4-single-positive T cells, present in B cell-mediated autoimmunity and regarded as “extrafollicular” helper T cells, were rare throughout the response, despite prominent extrafollicular B cell responses, revealing fundamental differences in autoimmune- and infection-induced T-dependent B cell responses. While all ICOS+ subsets induced similar antibody levels in vitro, CXCR5-single-positive T cells were superior in inducing B cell proliferation. The regulation of T cell localization, marked by the single and coexpression of CXCR4 and CXCR5, might be an important determinant of TFH function.
doi:10.1128/JVI.06904-11
PMCID: PMC3416343  PMID: 22532671
15.  CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo 
Cellular immunology  2009;259(2):177-184.
Previous work has shown ICOS can function independently of CD28, but whether either molecule can compensate for the other in vivo is not known. Since ICOS is a potent inducer of Th2 cytokines and linked to allergy and elevated serum IgE in humans, we hypothesized that augmenting ICOS costimulation in murine allergic airway disease may overcome CD28 deficiency. While ICOS was expressed on T cells from CD28−/− mice, Th2-mediated airway inflammation was not induced in CD28−/− mice by increased ICOS costimulation. Further, we determined if augmenting CD28 costimulation could compensate for ICOS deficiency. ICOS−/− mice had a defect in airway eosinophilia that was not overcome by augmenting CD28 costimulation. CD28 costimulation also did not fully compensate for ICOS for antibody responses, germinal center formation or the development of follicular B helper T cells. CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo.
doi:10.1016/j.cellimm.2009.06.013
PMCID: PMC2748173  PMID: 19646680
Costimulation; CD28; ICOS; follicular B helper T cells; Rodent; Th2 Cells; Antibodies; Allergy; Asthma
16.  Inducible costimulator is essential for collagen-induced arthritis 
Journal of Clinical Investigation  2003;111(5):701-706.
CD4+ helper Th cells play a major role in the pathogenesis of rheumatoid arthritis. Th cell activation, differentiation, and immune function are regulated by costimulatory molecules. Inducible costimulator (ICOS) is a novel costimulatory receptor expressed on activated T cells. We, as well as others, recently demonstrated its importance in Th2 cytokine expression and Ab class switching by B cells. In this study, we examined the role of ICOS in rheumatoid arthritis using a collagen-induced arthritis model. We found that ICOS knockout mice on the DBA/1 background were completely resistant to collagen-induced arthritis and exhibited absence of joint tissue inflammation. These mice, when immunized with collagen, exhibited reduced anti-collagen IgM Ab’s in the initial stage and IgG2a Ab’s at the effector phase of collagen-induced arthritis. Furthermore, ICOS regulates the in vitro and in vivo expression of IL-17, a proinflammatory cytokine implicated in rheumatoid arthritis. These data indicate that ICOS is essential for collagen-induced arthritis and may suggest novel means for treating patients with rheumatoid arthritis.
doi:10.1172/JCI200317321
PMCID: PMC151904  PMID: 12618524
17.  Induction of Protective Cytotoxic T Cell Responses in the Presence of High Titers of  Virus-neutralizing Antibodies: Implications for Passive and Active Immunization  
The effect of preexistent virus-neutralizing antibodies on the active induction of antiviral T cell responses was studied in two model infections in mice. Against the noncytopathic lymphocytic choriomeningitis virus (LCMV), pretreatment with neutralizing antibodies conferred immediate protection against systemic virus spread and controlled the virus below detectable levels. However, presence of protective antibody serum titers did not impair induction of antiviral cytotoxic T lymphocyte (CTL) responses after infection with 102 PFU of LCMV. These CTLs efficiently protected mice independent of antibodies against challenge with LCMV–glycoprotein recombinant vaccinia virus; they also protected against otherwise lethal lymphocytic choriomeningitis caused by intracerebral challenge with LCMV-WE, whereas transfused antibodies alone did not protect, and in some cases even enhanced, lethal lymphocytic choriomeningitis. Against the cytopathic vesicular stomatitis virus (VSV), specific CTLs and Th cells were induced in the presence of high titers of VSV-neutralizing antibodies after infection with 106 PFU of VSV, but not at lower virus doses. Taken together, preexistent protective antibody titers controlled infection but did not impair induction of protective T cell immunity. This is particularly relevant for noncytopathic virus infections since both virus-neutralizing antibodies and CTLs are essential for continuous virus control. Therefore, to vaccinate against such viruses parallel or sequential passive and active immunization may be a suitable vaccination strategy to combine advantages of both virus-neutralizing antibodies and CTLs.
PMCID: PMC2212147  PMID: 9463415
18.  Plasmacytoid Dendritic Cells Promote Immunosuppression in Ovarian Cancer via ICOS Costimulation of Foxp3+ T-Regulatory Cells 
Cancer research  2012;72(20):5240-5249.
Epithelial ovarian cancer (EOC) is the fifth most common cause of cancer death among women. Despite its immunogenicity, effective antitumor responses are limited, due, in part, to the presence of forkhead box protein 3–positive (Foxp3+) T regulatory (Treg) cells in the tumor microenvironment. However, the mechanisms that regulate the accumulation and the suppressive function of these Foxp3+ Treg cells are poorly understood. Here, we found that the majority of Foxp3+ Treg cells accumulating in the tumor microenvironment of EOCs belong to the subset of Foxp3+ Treg cells expressing inducible costimulator (ICOS). The expansion and the suppressive function of these cells were strictly dependent on ICOS-L costimulation provided by tumor plasmacytoid dendritic cells (pDC). Accordingly, ICOS+Foxp3+Treg cells were found to localize in close vicinity of tumor pDCs, and their number directly correlated with the numbers of pDCs in the tumors. Furthermore, pDCs and ICOS+ Foxp3+Treg cells were found to be strong predictors for disease progression in patients with ovarian cancer, with ICOS+Treg cell subset being a stronger predictor than total Foxp3+Treg cells. These findings suggest an essential role for pDCs and ICOS-L in immunosuppression mediated by ICOS+ Foxp3+ Treg cells, leading to tumor progression in ovarian cancer.
doi:10.1158/0008-5472.CAN-12-2271
PMCID: PMC3652570  PMID: 22850422
19.  Upregulation of ICOS on CD43+ CD4+ murine small intestinal intraepithelial lymphocytes during acute reovirus infection 
Murine intestinal intraepithelial lymphocytes (IELs) can be classified according to expression of a CD43 glycoform recognized by the S7 monoclonal antibody. In this study, we examined the response of S7+ and S7- IELs in mice during acute reovirus serotype 3 (Dearing strain) infection, which was confirmed by virus-specific real-time PCR. In vivo proliferation increased significantly for both S7- and S7+ IELs on day 4 post-infection as determined by BrdU incorporation; however, expression of the inducible costimulatory (ICOS) molecule, which peaked on day 7 post-infection, was upregulated on S7+ CD4+ T cells, most of which were CD4+8- IELs. In vitro ICOS stimulation by syngeneic peritoneal macrophages induced IFN-γ secretion from IELs from day 7 infected mice, and was suppressed by treatment with anti-ICOS mAb. Additionally, IFN-γ mRNA increased in CD4+ IELs on day 6 post-infection. These findings indicate that S7- and S7+ IELs are differentially mobilized during the immune response to reovirus infection; that the regulated expression of ICOS is associated with S7+ IELs; and that stimulation of IELs through ICOS enhances IFN-γ synthesis during infection.
doi:10.1016/j.bbrc.2006.02.031
PMCID: PMC2894703  PMID: 16500623
Cell activation; Cell surface molecule; Intestinal; T cell; Rodent; Viral
20.  Virus-triggered immune suppression in mice caused by virus-specific cytotoxic T cells 
The Journal of Experimental Medicine  1988;167(5):1749-1754.
Normal mice infected with 10(5) infectious doses of lymphocytic choriomeningitis virus (LCMV, WE isolate) generated a reduced or no T cell-independent IgM and/or T cell-dependent IgG response to a subsequent vesicular stomatitis virus Indiana (VSV-IND) injection; this transient immune suppression lasted for weeks to months. Connatally infected LCMV-carrier mice or acutely infected T cell-deficient nude mice had normal anti-VSV IgM and IgG or IgM responses respectively. LCMV-infected nude mice transfused with helper cell-depleted LCMV- specific immune spleen cells were immunosuppressed. Normal mice infected with LCMV but treated with a rat anti-CD8 mAb (that had been shown previously to eliminate cytotoxic T cells in vivo) and then infected with VSV exhibited a normal anti-VSV IgM and IgG response. Since no IFN-alpha or -beta was detected on, or after, day 6 of LCMV infection, neither LCMV alone, nor IFN induced by it caused the observed immune suppression; the presented evidence suggests that LCMV- immune CD8+ T cells were responsible for it. It is conceivable that a similar pathogenesis where virus-specific cytotoxic T cells may destroy virus-infected cells essentially involved in an immune response (APC, T helper cells, etc.) may be involved in other virally triggered immune suppression or in AIDS.
PMCID: PMC2188942  PMID: 2966846
21.  Induction of ICOS+CXCR3+CXCR5+ TH Cells Correlates with Antibody Responses to Influenza Vaccination 
Science translational medicine  2013;5(176):176ra32.
Seasonal influenza vaccine protects 60 to 90% of healthy young adults from influenza infection. The immunological events that lead to the induction of protective antibody responses remain poorly understood in humans. We identified the type of CD4+ T cells associated with protective antibody responses after seasonal influenza vaccinations. The administration of trivalent split-virus influenza vaccines induced a temporary increase of CD4+ T cells expressing ICOS, which peaked at day 7, as did plasmablasts. The induction of ICOS was largely restricted to CD4+ T cells co-expressing the chemokine receptors CXCR3 and CXCR5, a subpopulation of circulating memory T follicular helper cells. Up to 60% of these ICOS+CXCR3+CXCR5+CD4+ T cells were specific for influenza antigens and expressed interleukin-2 (IL-2), IL-10, IL-21, and interferon-γ upon antigen stimulation. The increase of ICOS+CXCR3+CXCR5+CD4+ T cells in blood correlated with the increase of preexisting antibody titers, but not with the induction of primary antibody responses. Consistently, purified ICOS+CXCR3+CXCR5+CD4+ T cells efficiently induced memory B cells, but not naïve B cells, to differentiate into plasma cells that produce influenza-specific antibodies ex vivo. Thus, the emergence of blood ICOS+CXCR3+CXCR5+CD4+ T cells correlates with the development of protective antibody responses generated by memory B cells upon seasonal influenza vaccination.
doi:10.1126/scitranslmed.3005191
PMCID: PMC3621097  PMID: 23486778
22.  ICOS-Expressing Lymphocytes Promote Resolution of CD8-Mediated Lung Injury in a Mouse Model of Lung Rejection 
PLoS ONE  2013;8(8):e72955.
Acute rejection, a common complication of lung transplantation, may promote obliterative bronchiolitis leading to graft failure in lung transplant recipients. During acute rejection episodes, CD8+ T cells can contribute to lung epithelial injury but the mechanisms promoting and controlling CD8-mediated injury in the lung are not well understood. To study the mechanisms regulating CD8+ T cell–mediated lung rejection, we used a transgenic model in which adoptively transferred ovalbumin (OVA)-specific cytotoxic T lymphocytes (CTL) induce lung injury in mice expressing an ovalbumin transgene in the small airway epithelium of the lungs (CC10-OVA mice). The lung pathology is similar to findings in humans with acute lung transplant. In the presence of an intact immune response the inflammation resolves by day 30. Using CC10-OVA.RAG-/- mice, we found that CD4+ T cells and ICOS+/+ T cells were required for protection against lethal lung injury, while neutrophil depletion was not protective. In addition, CD4+Foxp3 + ICOS+ T cells were enriched in the lungs of animals surviving lung injury and ICOS+/+ Tregs promoted survival in animals that received ICOS-/- T cells. Direct comparison of ICOS-/- Tregs to ICOS+/+ Tregs found defects in vitro but no differences in the ability of ICOS-/- Tregs to protect from lethal lung injury. These data suggest that ICOS affects Treg development but is not necessarily required for Treg effector function.
doi:10.1371/journal.pone.0072955
PMCID: PMC3742557  PMID: 23967339
23.  B7 Costimulation Is Critical for Antibody Class Switching and CD8+ Cytotoxic T-Lymphocyte Generation in the Host Response to Vesicular Stomatitis Virus 
Journal of Virology  2000;74(1):203-208.
Antibody and cytotoxic T-lymphocyte (CTL) responses have critical roles in eliminating many viral infections. In addition to stimulation of the T-cell receptor, T cells require costimulatory signals to respond optimally. We evaluated the role of B7 costimulatory molecules (B7-1 and B7-2) in the immune response to viral infection using vesicular stomatitis virus (VSV) and mice lacking either B7-1 or B7-2 or both molecules. Mice lacking both B7-1 and B7-2 had essentially no anti-VSV immunoglobulin G1 (IgG1) response, decreased IgG2a responses, and normal IgM responses, while mice lacking either B7-1 or B7-2 had unaltered anti-VSV antibody responses compared to wild-type mice. Depletion of CD4+ cells further reduced the IgG2a response in mice lacking both B7 molecules, suggesting that CD4− cells may supply help for IgG2a in the absence of B7 costimulation. The absence of both B7 molecules profoundly reduced generation of both primary and secondary VSV-specific class I major histocompatibility complex (MHC)-restricted CTL, whereas VSV-specific CTL responses in mice lacking either B7-1 or B7-2 were similar to those of wild-type animals. Class I MHC-restricted CTL in wild-type mice were not dependent on CD4+ cells, suggesting that the failure of CTL in the absence of B7s is due to a lack of B7 costimulation directly to the CD8+ CTL. These data demonstrate that B7-1 and B7-2 have critical, overlapping functions in the antibody and CTL responses to this viral infection.
PMCID: PMC111529  PMID: 10590107
24.  Enhanced virus replication and inhibition of lymphocytic choriomeningitis virus disease in anti-gamma interferon-treated mice. 
Journal of Virology  1989;63(6):2813-2819.
The role of gamma interferon (IFN-gamma) induced during a viral infection in the ability of the host to acquire antiviral immunity was studied in mice. They were injected subcutaneously daily with an ammonium sulfate-precipitated sheep anti-IFN-gamma antibody preparation able to neutralize 10(4) U of IFN-gamma. Specificity of the anti-IFN-gamma antiserum was demonstrated by absence of detectable activity against natural IFN-alpha and -beta. Controls were treated with a similarly prepared normal sheep serum. Treatment with the IFN-gamma-specific antibody preparation had no influence on the ability of mice to generate anti-vaccinia virus- or anti-vesicular stomatitis virus (VSV)-specific cytotoxic T-cell (CTL) responses or T helper-dependent immunoglobulin G responses to VSV. In contrast, treatment of mice with sheep anti-IFN-gamma impaired CTL responses against lymphocytic choriomeningitis (LCM) virus (LCMV, Aggressive isolate); in addition, under the experimental conditions used, it prevented lethal LCM. Cytotoxic T-cell activity measured in the spleens of anti-IFN-gamma-treated mice was comparable to that found in mice initially infected with a 100-fold-larger dose of LCMV. Evaluation of the effects of treatment on the kinetics of virus replication revealed that in both euthymic and athymic nude C57BL/6 mice, anti-IFN-gamma treatment led to an increase of virus titers up to 100-fold compared with control mice. Therefore, IFN-gamma may play a role in controlling viruses with tropism for lymphocytes and monocytes/macrophages, such as LCMV.
PMCID: PMC250786  PMID: 2542591
25.  Age-dependent changes in the expression of regulatory cell surface ligands in activated human T-cells 
BMC Immunology  2013;14:45.
Background
The immune system consists of multiple preformed and more specific adaptive immune responses, which are all subject to both positive and negative regulation. Programmed cell death protein 1 (PD-1) is a cell surface ligand implicated in the induction of anergy, Inducible T-cell Costimulator (ICOS) plays a stimulatory role in the development of both CD4+ and CD8+ T-cells, Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) plays a role in inhibitory regulation of T-cell activity, and T cell immunoglobulin and mucin protein 3 (Tim-3) has been described as a negative regulatory molecule in CD4+ helper type 1 cells and CD8+ cytotoxic type 1 cells. Each of these ligands is induced with T-cell activation allowing greater opportunity to have a regulatory role.
Results
Flow cytometry was used to quantitate the expression of PD-1, ICOS, CTLA-4 and Tim-3 in human T-cells from geriatric and younger subjects both at baseline and after in vitro induction by mitogen. The magnitude of expression of the molecules increased significantly on activated blasts after mitogen stimulation compared to their baseline levels in resting cells. The increase in CTLA-4 expressing CD8+ T-cells was significantly higher after in vitro induction in older persons, while the increase in cells expressing Tim-3 and PD-1 was significantly reduced. In CD4+ T-cells, a greater increase in CTLA-4 expressing cells in older persons was the only difference between the age groups.
Conclusions
We found several significant changes in the older individuals in regulatory elements of the adaptive immune system that occur particularly after immune activation. These differences could have ramifications to autoimmunity as well as immunology against infection and tumors.
doi:10.1186/1471-2172-14-45
PMCID: PMC3850945  PMID: 24083425
Immunosenescence; CD4; CD8; Adaptive immune system; Anergy; Co-receptor; PD-1; CTLA-4; ICOS; Tim-3

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