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1.  Crystal structure of 2-(4-chloro­phen­yl)-2-oxoethyl 3-bromo­benzoate 
Packing in the title keto ester compound is dominated by the formation of inversion dimers by both non-classical hydrogen bonds and offset π–π stacking inter­actions.
2-(4-Chloro­phen­yl)-2-oxoethyl 3-bromo­benzoate, C15H10BrClO3, was synthesized in a single-step reaction by condensation of 3-bromo­benzoic acid with 2-bromo-1-(4-chloro­phen­yl)ethanone in di­methyl­formamide in the presence of tri­ethyl­amine as a catalyst. The structure consists of an aryl ketone moiety linked to an aryl ester unit by a methyl­ene group. Both units are reasonably planar (r.m.s. deviations of 0.119 and 0.010 Å for the aryl ketone and aryl ester units, respectively) and are almost orthogonal, with an angle of 88.60 (3)° between them. In the crystal, mol­ecules form five separate sets of inversion dimers. Three of these are generated by two C—H⋯O inter­actions and a C—H⋯Br contact, and form chains along c and along the ab cell diagonal. In addition, two inversion-related π–π stacking inter­actions between like aryl rings again form chains of mol­ecules but in this instance along the bc diagonal. These contacts generate infinite layers of mol­ecules parallel to (011) and stack the mol­ecules along the a-axis direction.
PMCID: PMC4257351  PMID: 25484728
crystal structure; 2-(4-chloro­phen­yl)-2-oxoethyl 3-bromo­benzoate; synthesis; π–π inter­actions; inversion dimers
2.  CD40 Signaling to the Rescue: A CD8 Exhaustion Perspective in Chronic Infectious Diseases 
Critical reviews in immunology  2013;33(4):361-378.
Chronic infectious diseases such as HIV, HBV, and HCV, among others, cause severe morbidity and mortality globally. Progressive decline in CD8 functionality, survival, and proliferative potential—a phenomenon referred to as CD8 exhaustion—is believed to be responsible for poor pathogen control in chronic infectious diseases. While the role of negative inhibitory receptors such as PD-1 in augmenting CD8 exhaustion has been extensively studied, the role of positive costimulatory receptors remains poorly understood. In this review, we discuss how one such costimulatory pathway, CD40–CD40L, regulates CD8 dysfunction and rescue. While the significance of this pathway has been extensively investigated in models of autoimmunity, acute infectious diseases, and tumor models, the role played by CD40–CD40L in regulating CD8 exhaustion in chronic infectious diseases is just beginning to be understood. Considering that monotherapy with blocking antibodies targeting inhibitory PD-1-PD-L1 pathway is only partially effective at ameliorating CD8 exhaustion and that humanized CD40 agonist antibodies are currently available, a better understanding of the role of the CD40–CD40L pathway in chronic infectious diseases will pave the way for the development of more robust immunotherapeutic and prophylactic vaccination strategies.
PMCID: PMC4051158  PMID: 23971530
PD-1; CD8 exhaustion; CD40; infectious disease
3.  The CD8 T-cell road to immunotherapy of toxoplasmosis 
Immunotherapy  2011;3(6):789-801.
Toxoplasma gondii infection induces a robust CD8 T-cell immunity that is critical for keeping chronic infection under control. In studies using animal models, it has been demonstrated that the absence of this response can compromise the host ability to keep chronic infection under check. Therapeutic agents that facilitate the induction and maintenance of CD8 T-cell response against the pathogen need to be developed. In the last decade, major strides in understanding the development of effector and memory response, particularly in viral and tumor models, have been made. However, factors involved in the generation of effector or memory response against T. gondii infection have not been extensively investigated. This information will be invaluable in designing immunotherapeutic regimens needed for combating this intracellular pathogen that poses a severe risk for pregnant women and immunocompromised individuals.
PMCID: PMC4051159  PMID: 21668315
CD8 T cells; IFN-γ; IL-12; IL-15; immunotherapy; infection; Tcm; Tem; Toxoplasma gondii
4.  Psychiatric Disorders in Toxoplasma Seropositive Patients—The CD8 Connection 
Schizophrenia Bulletin  2013;39(3):485-489.
Although the highest numbers of studies linking an infectious agent with schizophrenia has involved the parasite Toxoplasma gondii, the mechanistic underpinnings of this correlation has remained unaddressed. Incidentally, CD8 T cells, which play a pivotal role in mediating long-term immunity to Toxoplasma, are downregulated in schizophrenia patients. Recent studies have demonstrated that CD8 response is also impaired during chronic toxoplasmosis in murine models. In light of these new findings, in this article, we discuss the potential role of CD8 T cells in causing altered mental status in Toxoplasma seropositive schizophrenia patients.
PMCID: PMC3627775  PMID: 23427221
Toxoplasma; CD8 T cells; exhaustion; PD-1; schizophrenia
5.  Intrinsic TGF-β signaling promotes age-dependent CD8+ T cell polyfunctionality attrition 
The Journal of Clinical Investigation  2014;124(6):2441-2455.
Advanced age is associated with immune system deficits that result in an increased susceptibility to infectious diseases; however, specific mediators of age-dependent immune dysfunction have not been fully elucidated. Here we demonstrated that aged mice exhibit poor effector CD8+ T cell polyfunctionality, primarily due to CD8+ T cell–extrinsic deficits, and that reduced CD8+ T cell polyfunctionality correlates with increased susceptibility to pathogenic diseases. In aged animals challenged with the parasite Encephalitozoon cuniculi, effector CD8+ T cell survival and polyfunctionality were suppressed by highly elevated TGF-β1. Furthermore, TGF-β depletion reduced effector CD8+ T cell apoptosis in both young and aged mice and enhanced effector CD8+ T cell polyfunctionality in aged mice. Surprisingly, intrinsic blockade of TGF-β signaling in CD8+ T cells was sufficient to rescue polyfunctionality in aged animals. Together, these data demonstrate that low levels of TGF-β1 promote apoptosis of CD8+ effector T cells and high TGF-β1 levels associated with age result in both CD8+ T cell apoptosis and an altered transcriptional profile, which correlates with loss of polyfunctionality. Furthermore, elevated TGF-β levels are observed in the elderly human population and in aged Drosophila, suggesting that TGF-β represents an evolutionarily conserved negative regulator of the immune response in aging organisms.
PMCID: PMC4038564  PMID: 24762437
6.  Donor CD8+ T Cells Prevent Toxoplasma gondii De-Encystation but Fail To Rescue the Exhausted Endogenous CD8+ T Cell Population 
Infection and Immunity  2013;81(9):3414-3425.
Functional exhaustion of CD8+ T cells due to increased expression of inhibitory molecule PD-1 (Programmed Death-1) causes reactivation of latent disease during later phases of chronic toxoplasmosis. Onset of disease recrudescence results in decreased parasite cyst burden concomitant with parasites undergoing stage conversion from a primarily encysted, quiescent bradyzoite to a fast-replicating, highly motile tachyzoite. Thus, reduced cyst burden is one of the early hallmarks of disease recrudescence. This was further validated by depleting gamma interferon (IFN-γ), a cytokine known to control latent toxoplasmosis, in chronically infected prerecrudescent mice. Since CD8+ T cells (an important source of IFN-γ) lose their functionality during the later phases of chronic toxoplasmosis, we next examined if adoptive transfer of functional CD8+ T cells from acutely infected donors to the chronically infected prerecrudescent hosts could impede parasite de-encystation and rescue exhausted CD8+ T cells. While the transfer of immune CD8+ T cells temporarily restricted the breakdown of cysts, the exhausted endogenous CD8+ T cell population was not rescued. Over time, the donor population got deleted, resulting in parasite de-encystation and host mortality. Considering that donor CD8+ T cells fail to become long-lived, one of the cardinal features of memory CD8+ T cells, it bears the implication that memory CD8 differentiation is impaired during chronic toxoplasmosis. Moreover, our data strongly suggest that while adoptive immunotherapy can prevent parasite de-encystation transiently, reduced antigen burden in the chronic phase by itself is insufficient for rescue of exhausted CD8+ T cells. The conclusions of this study have profound ramifications in designing immunotherapeutics against chronic toxoplasmosis.
PMCID: PMC3754203  PMID: 23817617
7.  IL-7 and IL-15 does not synergize during CD8 T cell recall response against an obligate intracellular parasite 
Long-term protection against Toxoplasma gondii is dependent on robust CD8+ T cell immunity. In the absence of this response, the host is unable to maintain chronicity, which results in recrudescence of infection and possible death. Factors needed for the persistence of protective CD8+ T cells against the parasite need to be evaluated. Previous studies from our laboratory have reported that synergism between γ chain cytokines like IL-7 and IL-15 is critical for the generation of CD8+ T cell response needed for protection during acute infection. In this study we report that the situation is different during the recall response where CD8+ T cell response is almost entirely dependent on IL-15, with IL-7 at best playing a minor role. In the absence of IL-15, CD8+ T cells fail to respond optimally to parasitic re-challenge and hosts are unable to control their replication, which leads to their death. Thus T. gondii infection may represent a unique situation where CD8+ T cell response during secondary challenge is primarily dependent on IL-15 with other γ chain cytokines having nominal effect. These findings provide important information regarding factors involved in the generation of protective immunity against T.gondii with strong implications in developing immunotherapeutic agents against the pathogen.
PMCID: PMC3768286  PMID: 22885140
Toxoplasma gondii; CD8+ T cells; IL-15; IL-7
8.  T Cell exhaustion in protozoan disease 
Trends in parasitology  2012;28(9):377-384.
Protozoan parasites cause severe morbidity and mortality in humans worldwide, especially in developing countries where access to chemotherapeutic agents is limited. Although parasites initially evoke a robust immune response, subsequent immunity fails to clear infection, ultimately leading to the chronic stage. This enigmatic situation was initially addressed in chronic viral models, where T cells lose their function, a phenomenon referred to as ’exhaustion‘. However, recent studies demonstrate that this paradigm can be extended to protozoan diseases as well, albeit with notable differences. These studies have revealed that T cell responses generated against Toxoplasma gondii, Plasmodium sp. and Leishmania sp. can become dysfunctional. This Review discusses T cell exhaustion in parasitic infection, mechanisms of development, and a possible role in disease outcome.
PMCID: PMC3768288  PMID: 22832368
protozoan; exhaustion; parasite; Toxoplasma; Leishmania; Plasmodium; T cell
9.  PD-1–Mediated Attrition of Polyfunctional Memory CD8+ T Cells in Chronic Toxoplasma Infection 
The Journal of Infectious Diseases  2012;206(1):125-134.
We reported earlier that during chronic toxoplasmosis CD8+ T cells become functionally exhausted with concomitant PD-1 upregulation, leading to eventual host mortality. However, how immune exhaustion specifically mediates attrition of CD8 polyfunctionality, a hallmark of potent T-cell response, during persistent infections has not been addressed. In this study, we demonstrate that PD-1 is preferentially expressed on polyfunctional memory CD8+ T cells, which renders them susceptible to apoptosis. In vitro blockade of the PD-1–PD-L1 pathway dramatically reduces apoptosis of polyfunctional and interferon γ+/granzyme B− memory but not effector CD8+ T cells. In summary, the present report underscores the critical role of the PD-1–PD-L1 pathway in mediating attrition of this important CD8+ T-cell subset and addresses the mechanistic basis of how αPD-L1 therapy reinvigorates polyfunctional CD8 response during chronic infections. The conclusions of this study can have profound immunotherapeutic implications in combating recrudescent toxoplasmosis as well other chronic infections.
PMCID: PMC3415930  PMID: 22539813
10.  2-(4-Methyl­phen­yl)-2-oxoethyl 3-bromo­benzoate 
The mol­ecule of the title compound, C16H13BrO3, is built of two approximately planar fragments, viz. 3-bromo­benzoate [maximum deviation = 0.055 (2) Å and 2-oxo-2-p-tolyl­ethyl [maximum deviation = 0.042 (2) Å], inclined by 46.51 (7)°. In the crystal, weak C—H⋯O hydrogen bonds and Br⋯Br contacts [3.6491 (7) Å] connect the mol­ecules into infinite layers parallel to (-221).
PMCID: PMC3589039  PMID: 23476275
11.  Immune correlates of aging in outdoor-housed captive rhesus macaques (Macaca mulatta) 
Questions remain about whether inflammation is a cause, consequence, or coincidence of aging. The purpose of this study was to define baseline immunological characteristics from blood to develop a model in rhesus macaques that could be used to address the relationship between inflammation and aging. Hematology, flow cytometry, clinical chemistry, and multiplex cytokine/chemokine analyses were performed on a group of 101 outdoor-housed captive rhesus macaques ranging from 2 to 24 years of age, approximately equivalent to 8 to 77 years of age in humans.
These results extend earlier reports correlating changes in lymphocyte subpopulations and cytokines/chemokines with increasing age. There were significant declines in numbers of white blood cells (WBC) overall, as well as lymphocytes, monocytes, and polymorphonuclear cells with increasing age. Among lymphocytes, there were no significant declines in NK cells and T cells, whereas B cell numbers exhibited significant declines with age. Within the T cell populations, there were significant declines in numbers of CD4+ naïve T cells and CD8+ naïve T cells. Conversely, numbers of CD4+CD8+ effector memory and CD8+effector memory T cells increased with age. New multiplex analyses revealed that concentrations of a panel of ten circulating cytokines/chemokines, IFNγ, IL1b, IL6, IL12, IL15, TNFα, MCP1, MIP1α, IL1ra, and IL4, each significantly correlated with age and also exhibited concordant pairwise correlations with every other factor within this group. To also control for outlier values, mean rank values of each of these cytokine concentrations in relation to age of each animal and these also correlated with age.
A panel of ten cytokines/chemokines were identified that correlated with aging and also with each other. This will permit selection of animals exhibiting relatively higher and lower inflammation status as a model to test mechanisms of inflammation status in aging with susceptibility to infections and vaccine efficacy.
PMCID: PMC3541156  PMID: 23151307
Inflammation; Inflamm-aging; Cytokine; Chemokine; Multiplex; Rhesus macaque; Aging; Animal model; Immune senescence; Blood
12.  CD40-CD40L pathway plays a critical CD8 intrinsic and extrinsic role during rescue of exhausted CD8 T cells 
CD8 exhaustion mediated by inhibitory PD-1-PD-L1 pathway occurs in several chronic infections including toxoplasmosis. While blockade of PD-1-PD-L1 pathway revives this response, the role of co-stimulatory receptors involved in this rescue has not been ascertained in any model of CD8 exhaustion. This is the first report which demonstrates that one such co-stimulatory pathway, CD40-CD40L, plays a critical role during rescue of exhausted CD8 T cells. Blockade of this pathway abrogates the ameliorative effects of αPD-L1 treatment on CD8 T cells. Additionally, this is the first report which demonstrates, in an infectious disease model, that CD8 intrinsic CD40 signaling is important for optimal CD8 polyfunctionality, proliferation, T-bet upregulation and IL-21 signaling, albeit in the context of CD8 rescue. The critical role of CD40 during the rescue of exhausted CD8 T cells may provide a rational basis for designing novel therapeutic vaccination approaches.
PMCID: PMC3197960  PMID: 21949017
13.  Redefining Chronic Toxoplasmosis—A T Cell Exhaustion Perspective 
PLoS Pathogens  2012;8(10):e1002903.
PMCID: PMC3469626  PMID: 23071434
14.  Gastrointestinal Cell Mediated Immunity and the Microsporidia 
PLoS Pathogens  2012;8(7):e1002775.
PMCID: PMC3395611  PMID: 22807673
15.  Reactive nitrogen and oxygen species, and iron sequestration contribute to macrophage-mediated control of Encephalitozoon cuniculi (Phylum Microsporidia) infection in vitro and in vivo 
Microbes and infection / Institut Pasteur  2010;12(14-15):1244-1251.
Encephalitozoon cuniculi (Phylum Microsporidia) infects a wide range of mammals, and replicates within resting macrophages. Activated macrophages, conversely, inhibit replication and destroy intracellular organisms. These studies were performed to assess mechanisms of innate immune responses expressed by macrophages to control E. cuniculi infection. Addition of reactive oxygen and nitrogen species inhibitors to activated murine peritoneal macrophages statistically significantly, rescued E. cuniculi infection ex vivo. Mice deficient in reactive oxygen species, reactive nitrogen species, or both survived ip inoculation of E. cuniculi, but carried significantly higher peritoneal parasite burdens than wild-type mice at 1 and 2 weeks post inoculation. Infected peritoneal macrophages could still be identified 4 weeks post inoculation in mice deficient in reactive nitrogen species. L-tryptophan supplementation of activated murine peritoneal macrophage cultures ex vivo failed to rescue microsporidia infection. Addition of ferric citrate to supplement iron, however, did significantly rescue E. cuniculi infection in activated macrophages and further increased parasite replication in non-activated macrophages over non-treated resting control macrophages. These results demonstrate the contribution of reactive oxygen and nitrogen species, as well as iron sequestration, to innate immune responses expressed by macrophages to control E. cuniculi infection.
PMCID: PMC2998546  PMID: 20888426
Microsporidia; parasites; parasite–host interactions; innate immunity; reactive nitrogen species; reactive oxygen species; peritoneal macrophages
16.  Statistical Analysis of the Different Factors Affecting the Diarrhea 
Acta Informatica Medica  2011;19(3):158-160.
Diarrhea is a worldwide problem facing both developing countries and developed countries, especially in pediatric population. Because of shortage of health facilities and lack of good food in developing countries, it is known fact that developing countries are facing this death taking problem more. The main purpose of this study was to examine the various factors which affect the recovery time of diarrhea. A multiple linear regression was applied to analyze the data and to select a model. The response variable for the study was the recovery time of diarrhea. The results of the analysis show that the Zinc is the main factor which affect the recovery time in Peshawar.
PMCID: PMC3564179  PMID: 23408274
Diarrhea; Zinc; Multiple Regression; Sex.
17.  Purified PTP1 protein induce antigen specific protective immunity against E. cuniculi 
Microsporidiosis poses a problem for immunocompromised individuals including patients with HIV infection as well as those with organ transplantation. Recent reports from Africa have suggested that microsporidiosis with diarrhea is an independent risk factor for malnutrition in children. Previous studies from our laboratory have demonstrated that CD8+ T cells are an essential component of protective immunity against the microsporidium Encephalitozoon cuniculi. Mutant mice lacking this T cell subset or cytotoxic function are unable to clear the infection and ultimately succumb to the disease. However, information regarding the antigens involved in the elicitation of CD8+ T cell response is not available. In this study, we report that immunization of animals with Encephalitozoon hellem polar tube protein 1 (rEhPTP1) induces a strong T cell response in vaccinated animals. Splenic dendritic cells pulsed with rEhPTP1 are able to induce E. cuniculi specific CD8+ T cell response with no effect on the CD4+ T cell subset. This is the first report identifying a protein capable of inducing CD8+ T cell immunity, which is conserved in other microsporidial species of human importance.
PMCID: PMC2894705  PMID: 20348007
Microsporidia; T cells; Immunization
18.  Active hepatitis C infection and HCV genotypes prevalent among the IDUs of Khyber Pakhtunkhwa 
Virology Journal  2011;8:327.
Injection drug users (IDUs) are considered as a high risk group to develop hepatitis C due to needle sharing. In this study we have examined 200 injection drug users from various regions of the Khyber Pakhtunkhwa province for the prevalence of active HCV infection and HCV genotypes by Immunochromatographic assays, RT-PCR and Type-specific PCR. Our results indicated that 24% of the IDUs were actively infected with HCV while anti HCV was detected among 31.5% cases. Prevalent HCV genotypes were HCV 2a, 3a, 4 and 1a. Majority of the IDUs were married and had attained primary or middle school education. 95% of the IDUs had a previous history of needle sharing. Our study indicates that the rate of active HCV infection among the IDUs is higher with comparatively more prevalence of the rarely found HCV types in KPK. The predominant mode of HCV transmission turned out to be needle sharing among the IDUs.
PMCID: PMC3148566  PMID: 21711541
IDUs; HCV; Genotype; RT-PCR; KPK
19.  Plasmacytoid DC from Aged Mice Down-Regulate CD8 T Cell Responses by Inhibiting cDC Maturation after Encephalitozoon cuniculi Infection 
PLoS ONE  2011;6(6):e20838.
Age associated impairment of immune function results in inefficient vaccination, tumor surveillance and increased severity of infections. Several alterations in adaptive immunity have been observed and recent studies report age related declines in innate immune responses to opportunistic pathogens including Encephalitozoon cuniculi. We previously demonstrated that conventional dendritic cells (cDC) from 9-month-old animals exhibit sub-optimal response to E. cuniculi infection, suggesting that age associated immune senescence begins earlier than expected. We focused this study on how age affects plasmacytoid DC (pDC) function. More specifically how aged pDC affect cDC function as we observed that the latter are the predominant activators of CD8 T cells during this infection. Our present study demonstrates that pDC from middle-aged mice (12 months) suppress young (8 week old) cDC driven CD8 T cell priming against E. cuniculi infection. The suppressive effect of pDC from older mice decreased maturation of young cDC via cell contact. Aged mouse pDC exhibited higher expression of PD-L1 and blockade of their interaction with cDC via this molecule restored cDC maturation and T cell priming. Furthermore, the PD-L1 dependent suppression of cDC T cell priming was restricted to effector function of antigen-specific CD8 T cells not their expansion. To the best of our knowledge, the data presented here is the first report highlighting a cell contact dependent, PD-L1 regulated, age associated defect in a DC subpopulation that results in a sub-optimal immune response against E. cuniculi infection. These results have broad implications for design of immunotherapeutic approaches to enhance immunity for aging populations.
PMCID: PMC3112225  PMID: 21695169
20.  IFN-γ-Producing Dendritic Cells Are Important for Priming of Gut Intraepithelial Lymphocyte Response Against Intracellular Parasitic Infection1 
The importance of intraepithelial lymphocytes (IEL) in immunoprotection against orally acquired pathogens is being increasingly recognized. Recent studies have demonstrated that Ag-specific IEL can be generated and can provide an important first line of defense against pathogens acquired via oral route. However, the mechanism involved in priming of IEL remains elusive. Our current study, using a microsporidial model of infection, demonstrates that priming of IEL is dependent on IFN-γ-producing dendritic cells (DC) from mucosal sites. DC from mice lacking the IFN-γ gene are unable to prime IEL, resulting in failure of these cells to proliferate and lyse pathogen-infected targets. Also, treatment of wild-type DC from Peyer’s patches with Ab to IFN-γ abrogates their ability to prime an IEL response against Encephalitozoon cuniculi in vitro. Moreover, when incubated with activated DC from IFN-γ knockout mice, splenic CD8+ T cells are not primed efficiently and exhibit reduced ability to home to the gut compartment. These data strongly suggest that IFN-γ-producing DC from mucosal sites play an important role in the generation of an Ag-specific IEL response in the small intestine. To our knowledge, this report is the first demonstrating a role for IFN-γ-producing DC from Peyer’s patches in the development of Ag-specific IEL population and their trafficking to the gut epithelium.
PMCID: PMC3109618  PMID: 17675510
21.  Immune response to Encephalitozoon cuniculi infection 
Microsporidia are obligate intracellular parasites, which can cause complications in immunocompromised individuals. Very little is known about the host immune response generated against these infectious agents. Encephalitozoon cuniculi is the best studied microsporidian and the protective immune response against this parasite is mediated by cytotoxic CD8+ T cells.
PMCID: PMC3109655  PMID: 11369277
22.  CD8 T Cells and Toxoplasma gondii: A New Paradigm 
CD8 T cells are essential for control of Toxoplasma gondii infection. Once activated they undergo differentiation into short-lived effector and memory precursor effector cells. As effector cells, CD8 T cells exert immune pressure on the parasite via production of inflammatory cytokines and through their cytolytic activity. Once immune control has been established, the parasite encysts and develops into chronic infection regulated by the memory CD8 T-cell population. Several signals are needed for this process to be initiated and for development of fully differentiated memory CD8 T cells. With newly developed tools including CD8 T-cell tetramers and TCR transgenic mice, dissecting the biology behind T. gondii-specific CD8 T-cell responses can now be more effectively addressed. In this paper, we discuss what is known about the signals required for effective T. gondii-specific CD8 T-cell development, their differentiation, and effector function.
PMCID: PMC3112509  PMID: 21687650
23.  Induction of a Rapid and Strong Antigen-Specific Intraepithelial Lymphocyte Response during Oral Encephalitozoon cuniculi Infection1 
Encephalitozoon cuniculi continues to pose a problem for immunocompromised patients. Previous studies from our laboratory have elucidated the importance of the CD8+ T cell subset in the protection against systemic parasite infection. There have been no studies related to the mucosal immunity induced against this orally acquired pathogen. In the present study, the immune response generated in the gut after oral E. cuniculi infection was evaluated. An early and rapid increase of the intraepithelial lymphocyte (IEL) population of orally infected animals was observed. This increase in the IEL population started as early as day 3 and peaked at day 7 postinfection with persistent elevation thereafter. At day 7 postinfection, IELs expressed strong cytokine messages (IFN-γ and IL-10) and were highly cytotoxic for parasite-infected syngeneic macrophages. At an E:T ratio of 80:1, these cells were able to cause >60% Ag-specific target cell lysis. A significant increase in the CD8αα subset of IEL in response to an oral E. cuniculi infection was observed. To the best of our knowledge, such an early expansion of an IEL population exhibiting strong ex vivo cytotoxicity has not been reported with infectious models. These data suggest that IELs act as important barriers for multiplication of this organism leading to the successful resolution of infection. The protective role of IELs may be due both to their inflammatory (IFN-γ production and cytotoxic response) as well as immunoregulatory (IL-10 production) properties.
PMCID: PMC3086354  PMID: 15034055
24.  Optimal CD8 T-Cell Response against Encephalitozoon cuniculi Is Mediated by Toll-Like Receptor 4 Upregulation by Dendritic Cells ▿  
Infection and Immunity  2010;78(7):3097-3102.
CD8+ T-cell immunity has been shown to play an important role in the protective immune response against Encephalitozoon cuniculi. Although earlier studies suggest that dendritic cells (DC) are important for the induction of this response, the factors responsible for initiation of the dendritic cell response against this pathogen have not been evaluated. In the current study, we demonstrate that E. cuniculi infection causes strong Toll-like receptor 4 (TLR4)-dependent dendritic cell activation and a blockade of this molecule reduces the ability of DC to prime an antigen-specific CD8+ T-cell response. Pretreatment of DC with anti-TLR4 antibody causes a defect in both in vitro and in vivo CD8+ T-cell priming. These findings, for the first time, emphasize the contribution of TLR4 in the induction of CD8+ T-cell immunity against E. cuniculi infection.
PMCID: PMC2897398  PMID: 20421379
25.  Lack of Interleukin-12 in p40-Deficient Mice Leads to Poor CD8+ T-Cell Immunity against Encephalitozoon cuniculi Infection▿  
Infection and Immunity  2010;78(6):2505-2511.
A CD8+ T-cell response is critical for protection against Encephalitozoon cuniculi infection. However, the factors responsible for the generation of CD8+ T-cell immunity during E. cuniculi infection and the cytokines involved in this process have not been identified. In the present study, we demonstrated that p40-deficient animals, which are unable to produce interleukin-12 (IL-12), have a serious defect in expansion of the CD8+ T-cell response which compromises the survival of an infected host. Adoptive transfer of CD8+ T cells from immunocompetent donors protected SCID mice infected with E. cuniculi, whereas administration of CD8+ T cells from p40−/− mice failed to protect infected SCID mice. In vitro dendritic cell (DC) cultures from knockout mice pulsed with E. cuniculi spores were unable to develop a robust CD8+ T-cell immune response. Addition of exogenous IL-12 or transfer of CD8+ T cells that were initially primed with DC from p40−/− animals to DC cultures from immunocompetent mice (directly or via transwells) led to optimal expansion of these cells. This IL-12-mediated reinstatement of CD8+ T-effector immunity was independent of gamma interferon (IFN-γ) as addition of antibody to the cultures failed to have an effect. These studies demonstrated that IL-12 plays a predominant role in the expansion of effector CD8+ T-cell immunity against E. cuniculi, which is critical for host survival. These findings are very important for understanding the protective immune mechanisms needed to protect an immunocompromised host against an opportunistic infection and can be extended to other microsporidial pathogens.
PMCID: PMC2876566  PMID: 20308292

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