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1.  Increased Th2 activity and diminished skin barrier function cooperate in allergic skin inflammation 
European journal of immunology  2016;46(11):2609-2613.
Atopic dermatitis (AD) is a chronic inflammatory skin disease induced by a complex interaction between susceptibility genes encoding skin barrier components and environmental allergen exposure that results in type 2 cytokine production. Although genetic lesions in either component can be risk factors for disease in patients, whether these pathways interact in the development of AD is not clear. To test this, we mated mice with T-cell specific expression of constitutively active Stat6 (Stat6VT) that spontaneously develop allergic skin inflammation with Flaky tail (Ft) mice that have mutations in Flg and Tmem79 genes that each affect skin barrier function. Our results demonstrate that over 90% of the Stat6VT transgenic mice carrying the Ft alleles (Stat6VTxFt−/−) develop severe atopic dermatitis lesions by 3-5 months of age, compared with only 40% of Stat6VT mice that develop disease by 6-7 months of age. Further, histopathological analysis of skin tissues from Stat6VTxFt−/− mice revealed extensive thickening of the dermis with increased inflammatory infiltrates as compared with Stat6VT mice. Our study suggests that skin barrier defects and altered Th2 responses independently cooperate in the pathogenesis of allergic skin inflammation, similar to effects observed in patients with AD.
doi:10.1002/eji.201646421
PMCID: PMC5142240  PMID: 27510401
allergic skin inflammation; atopic dermatitis; genetic lesions; Stat6; Th2 response
2.  Alcohol Policies and Suicide: A Review of the Literature 
Both intoxication and chronic heavy alcohol use are associated with suicide. There is extensive population-level evidence linking per capita alcohol consumption with suicide. While alcohol policies can reduce excessive alcohol consumption, the relationship between alcohol policies and suicide warrants a critical review of the literature.
This review summarizes the associations between various types of alcohol policies and suicide, both in the United States and internationally, as presented in English-language literature published between 1999 and 2014. Study designs, methodological challenges, and limitations in ascertaining the associations are discussed.
Because of the substantial between-states variation in alcohol policies, U.S.-based studies contributed substantially to the literature. Repeated cross-sectional designs at both the ecological level and decedent level were common among U.S.-based studies. Non-U.S. studies often used time series data to evaluate pre-post comparisons of a hybrid set of policy changes. Although inconsistency remained, the published literature in general supported the protective effect of restrictive alcohol policies on reducing suicide as well as the decreased level of alcohol involvement among suicide decedents. Common limitations included measurement and selection bias, and a focus on effects of a limited number of alcohol policies without accounting for other alcohol policies.
This review summarizes a number of studies that suggest restrictive alcohol policies may contribute to suicide prevention on a general population level, and to a reduction of alcohol involvement among suicide deaths.
doi:10.1111/acer.13203
PMCID: PMC5048547  PMID: 27618526
Alcohol Policies; Suicide; Blood Alcohol Content; Critical Review
3.  The ETS family transcription factors Etv5 and PU.1 function in parallel to promote Th9 cell development 
The IL-9-secreting Th9 subset of CD4 T helper cells develop in response to an environment containing IL-4 and TGFβ, promoting allergic disease, autoimmunity, and resistance to pathogens. We previously identified a requirement for the ETS family transcription factor PU.1 in Th9 development. In this report we demonstrate that the ETS transcription factor ETV5 promotes IL-9 production in Th9 cells by binding and recruiting histone acetyltransferases to the Il9 locus at sites distinct from PU.1. In cells that are deficient in both PU.1 and ETV5 there is lower IL-9 production than in cells lacking either factor alone. In vivo loss of PU.1 and ETV5 in T cells results in distinct affects on allergic inflammation in the lung, suggesting that these factors function in parallel. Together, these data define a role for ETV5 in Th9 development and extend the paradigm of related transcription factors having complementary functions during differentiation.
doi:10.4049/jimmunol.1502383
PMCID: PMC5010937  PMID: 27496971
4.  STAT3 activation impairs the stability of Th9 cells 
Th9 cells regulate multiple immune responses including immunity to pathogens and tumors, allergic inflammation, and autoimmunity. Despite ongoing research into Th9 development and function, little is known about the stability of the Th9 phenotype. In this report we demonstrate that IL-9 production is progressively lost in Th9 cultures over several rounds of differentiation. The loss of IL-9 is not due to an outgrowth of cells that do not secrete IL-9, as purified IL-9 secretors demonstrate the same loss of IL-9 in subsequent rounds of differentiation. The loss of IL-9 production correlates with increases in phospho-STAT3 levels within the cell, and the production of IL-10. STAT3-deficient Th9 cells have increased IL-9 production that is maintained for longer in culture than IL-9 in control cultures. IL-10 is responsible for STAT3 activation during the first round of differentiation, and contributes to instability in subsequent rounds of culture. Together, our results indicate that environmental cues dictate the instability of the Th9 phenotype, and suggest approaches to enhance Th9 activity in beneficial immune responses.
doi:10.4049/jimmunol.1601624
PMCID: PMC5340611  PMID: 28137893
5.  STAT3 activation impairs the stability of Th9 cells 
Th9 cells regulate multiple immune responses including immunity to pathogens and tumors, allergic inflammation, and autoimmunity. Despite ongoing research into Th9 development and function, little is known about the stability of the Th9 phenotype. In this report we demonstrate that IL-9 production is progressively lost in Th9 cultures over several rounds of differentiation. The loss of IL-9 is not due to an outgrowth of cells that do not secrete IL-9, as purified IL-9 secretors demonstrate the same loss of IL-9 in subsequent rounds of differentiation. The loss of IL-9 production correlates with increases in phospho-STAT3 levels within the cell, and the production of IL-10. STAT3-deficient Th9 cells have increased IL-9 production that is maintained for longer in culture than IL-9 in control cultures. IL-10 is responsible for STAT3 activation during the first round of differentiation, and contributes to instability in subsequent rounds of culture. Together, our results indicate that environmental cues dictate the instability of the Th9 phenotype, and suggest approaches to enhance Th9 activity in beneficial immune responses.
doi:10.4049/jimmunol.1601624
PMCID: PMC5340611  PMID: 28137893
7.  Mast Cells Regulate Epidermal Barrier Function and the Development of Allergic Skin Inflammation 
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by infiltration of eosinophils, T helper cells and mast cells. The role of mast cells in AD is not completely understood. To define the effects of mast cells on skin biology, we observed that mast cells regulate the homeostatic expression of Epidermal Differentiation Complex (EDC) and other skin genes. Decreased EDC gene expression in mice that genetically lack mast cells (KitW-sh/W-sh mice) is associated with increased uptake of protein antigens painted on the skin by dendritic cells, compared to similarly treated wild-type mice, suggesting a protective role for mast cells in exposure to nominal environmental allergens. To test this further, we crossed KitW-sh/W-sh mice with Stat6VT transgenic mice that develop spontaneous AD-like disease that is dependent on Th2 cytokines and associated with high serum concentrations of IgE. We observed that Stat6VT x KitW-sh/W-sh mice developed more frequent and more severe allergic skin inflammation than Stat6VT transgenic mice that had mast cells. Together, these studies suggest that mast cells regulate epidermal barrier function and have a potential protective role in the development of AD-like disease.
doi:10.1016/j.jid.2016.03.019
PMCID: PMC4921316  PMID: 27021404
8.  Heavy Alcohol Use Among Suicide Decedents Relative to a Nonsuicide Comparison Group: Gender-Specific Effects of Economic Contraction 
Background
The primary objective of this gender-stratified study was to assess the rate of heavy alcohol use among suicide decedents relative to a nonsuicide comparison group during the 2008-09 economic crisis.
Methods
The National Violent Death Reporting System and the Behavioral Risk Factor Surveillance System were analyzed by gender-stratified multiple logistic regression to test whether change in acute intoxication (blood alcohol content ≥ 0.08 g/dl) before (2005-07), during (2008-09), and after (2010-11) the Great Recession mirrored change in heavy alcohol use in a living sample.
Results
Among men, suicide decedents experienced a significantly greater increase (+8%) in heavy alcohol use at the onset of the recession (AOR=1.15, 95% confidence interval [CI]=1.10-1.20) (relative to the pre-recession period) than did men in a nonsuicide comparison group (−2%). Among women, changes in rates of heavy alcohol use were similar in the suicide and nonsuicide comparison groups at the onset and after the recession.
Conclusions
Acute alcohol use contributed to suicide among men during the recent economic downturn. Among women who died by suicide, acute alcohol use mirrored consumption in the general population. Women may show resilience (or men, vulnerability) to deleterious interaction of alcohol with financial distress.
doi:10.1111/acer.13100
PMCID: PMC4930372  PMID: 27187543
Suicide; Alcohol; Gender; Recession
9.  Ruptured Dissecting Intramural Duodenal Hematoma Following Endoscopic Retrograde Cholangiopancreatography 
A 34-year-old woman with schizophrenia developed abdominal pain. Ultrasound demonstrated cholelithiasis and a dilated biliary tree. The patient underwent endoscopic retrograde cholangiopancreatography (ERCP), sphincterotomy, and extraction of gallstones from the common bile duct. She developed post-procedure fever, tachycardia, and abdominal pain and was taken to the operating room for urgent cholecystectomy with intraoperative cholangiogram. At laparotomy, an intramural dissecting duodenal hematoma was discovered, which extended the length of the duodenum and ruptured. She underwent gastric pyloric exclusion, gastrojejunostomy, and healed uneventfully. ERCP is not without risks, and a degree of vigilance should be maintained in patients who develop new symptomatology following the procedure.
doi:10.14309/crj.2017.70
PMCID: PMC5449572
10.  STAT3 impairs STAT5 activation in the development of IL-9-secreting T cells 
T helper (Th) cell subsets develop in response to multiple activating signals, including the cytokine environment. IL-9-secreting T cells develop in response to the combination of IL-4 and TGF-β, though they clearly require other cytokine signals, leading to the activation of transcription factors including STAT5. In Th17 cells, there is a molecular antagonism of STAT5 with STAT3 signaling, though whether this paradigm exists in other Th subsets is not clear. In this report, we demonstrate that STAT3 attenuates the ability of STAT5 to promote the development of IL-9-secreting T cells. We demonstrate that production of IL-9 is increased in the absence of STAT3, and cytokines that result in a sustained activation of STAT3, including IL-6, have the greatest potency in repressing IL-9 production in a STAT3-dependent manner. Increased IL-9 production in the absence of STAT3 correlates with increased endogenous IL-2 production and STAT5 activation, and blocking IL-2 responses eliminates the difference in IL-9 production between wild type and STAT3-deficient T cells. Moreover, transduction of developing Th9 cells with a constitutively active STAT5 eliminates the ability of IL-6 to reduce IL-9 production. Thus, STAT3 functions as a negative regulator of IL-9 production through attenuation of STAT5 activation and function.
doi:10.4049/jimmunol.1501801
PMCID: PMC4821742  PMID: 26976954
11.  Key Role of STAT4 Deficiency in the Hematopoietic Compartment in Insulin Resistance and Adipose Tissue Inflammation 
Mediators of Inflammation  2017;2017:5420718.
Visceral adipose tissue (AT) inflammation is linked to the complications of obesity, including insulin resistance (IR) and type 2 diabetes. Recent data from our lab showed that germline deficiency in STAT4 reduces inflammation and improves IR in obese mice. The objective of this study was to determine the contribution of selective STAT4 deficiency in subsets of hematopoietic cells to IR and AT inflammation. To determine the contribution of hematopoietic lineage, we sublethally irradiated Stat4−/−C57Bl6 mice and reconstituted them with bone marrow cells (BMC) from Stat4+/+C57Bl6 congenic donors. We also established the contribution of selective STAT4 deficiency in CD4+ or CD8+ T cells using adoptive transfer in Rag1−/− mice. All mice received a HFD for 15 weeks (n = 7–12 mice/group). BMC that expressed STAT4 induced increases in glucose intolerance and IR compared to STAT4-deficient cells. Also, AT inflammation was increased and the numbers of CD8+ cells infiltrating AT were higher in mice with STAT4 expressing BMC. Studies in Rag1−/− mice further confirmed the prominent role of CD8+ cells expressing STAT4 in insulin resistance and AT and islet inflammation. Collectively our results show specific and dominant contribution of STAT4 in the hematopoietic compartment to metabolic health and inflammation in diet-induced obesity.
doi:10.1155/2017/5420718
PMCID: PMC5376449  PMID: 28400678
12.  The TNF-family ligand TL1A and its receptor DR3 promote T-cell mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9 producing T cells1 
The TNF family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation, and reduced ILC2-dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3 deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. Here we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9.
doi:10.4049/jimmunol.1401220
PMCID: PMC5112176  PMID: 25786692
13.  STAT4 Deficiency Reduces the Development of Atherosclerosis in mice 
Atherosclerosis  2015;243(1):169-178.
Atherosclerosis is a chronic inflammatory process that leads to plaque formation in large and medium sized vessels. T helper 1 (Th1) cells constitute the majority of plaque infiltrating pro-atherogenic T cells and are induced via IFNγ-dependent activation of T-box (Tbet) and/or IL-12-dependent activation of signal transducer and activator of transcription 4 (STAT4). We thus aimed to define a role for STAT4 in atherosclerosis. STAT4-deficiency resulted in a ~71% reduction (p<0.001) in plaque burden in Stat4−/−Apoe−/− vs Apoe−/− mice fed chow diet and significantly attenuated atherosclerosis (~31%, p<0.01) in western diet fed Stat4−/−Apoe−/− mice. Surprisingly, reduced atherogenesis in Stat4−/−Apoe−/− mice was not due to attenuated IFNγ production in vivo by Th1 cells, suggesting an at least partially IFNγ-independent pro-atherogenic role of STAT4. STAT4 is expressed in T cells, but also detected in macrophages (MΦs). Stat4−/−Apoe−/− in vitro differentiated M1 or M2 MΦs had reduced cytokine production compare to Apoe−/− M1 and M2 MΦs that was accompanied by reduced induction of CD69, I-Ab, and CD86 in response to LPS stimulation. Stat4−/−Apoe−/−MΦs expressed attenuated levels of CCR2 and demonstrated reduced migration toward CCL2 in a transwell assay. Importantly, the percentage of aortic CD11b+F4/80+Ly6Chi MΦs was reduced in Stat4−/−Apoe−/− vs Apoe−/− mice. Thus, this study identifies for the first time a pro-atherogenic role of STAT4 that is at least partially independent of Th1 cell-derived IFNγ, and primarily involving the modulation of MΦ responses.
doi:10.1016/j.atherosclerosis.2015.08.045
PMCID: PMC4636132  PMID: 26386214
Atherosclerosis; Inflammation; Leucocytes; Transcription factors
14.  Engineering a Therapeutic Lectin by Uncoupling Mitogenicity from Antiviral Activity 
Cell  2015;163(3):746-758.
Summary
A key effector route of the Sugar Code involves lectins that exert crucial regulatory controls by targeting distinct cellular glycans. We demonstrate that a single amino acid substitution in a banana lectin, replacing histidine 84 with a threonine, significantly reduces its mitogenicity while preserving its broad-spectrum antiviral potency. X-ray crystallography, NMR spectroscopy, and glycocluster assays reveal that loss of mitogenicity is strongly correlated with loss of pi-pi stacking between aromatic amino acids H84 and Y83, which removes a wall separating two carbohydrate binding sites, thus diminishing multivalent interactions. On the other hand, monovalent interactions and antiviral activity are preserved by retaining other wild-type conformational features and possibly through unique contacts involving the T84 side chain. Through such fine-tuning, target selection and downstream effects of a lectin can be modulated so as to knock down one activity while preserving another, thus providing tools for therapeutics and for understanding the Sugar Code.
doi:10.1016/j.cell.2015.09.056
PMCID: PMC4641746  PMID: 26496612
antiviral; β-prism; glycocluster; lectin; mitogenicity; stacking
15.  PU.1 expression in T follicular helper cells limits CD40L-dependent germinal center B cell development 
PU.1 is an ETS family transcription factor important for the development of multiple hematopoietic cell lineages. Previous work demonstrated a critical role for PU.1 in promoting Th9 development, and in limiting Th2 cytokine production. Whether PU.1 has functions in other T helper lineages is not clear. In this report we examined the effects of ectopic expression of PU.1 in CD4+T cells and observed decreased expression of genes involved with the function of T follicular helper (Tfh) cells, including Il21 and Tnfsf5 (encoding CD40L). T cells from conditional mutant mice that lack expression of PU.1 in T cells (Sfpi1lck−/−) demonstrated increased production of CD40L and IL-21 in vitro. Following adjuvant-dependent or adjuvant-independent immunization, we observed that Sfpi1lck−/− mice had increased numbers of Tfh cells, increased germinal center B cells, and increased antibody production in vivo. This correlated with increased expression of IL-21 and CD40L in Tfh cells from Sfpi1lck−/− mice, compared to control mice. Finally, although blockade of IL-21 did not affect germinal center B cells in Sfpi1lck−/− mice, anti-CD40L treatment of immunized Sfpi1lck−/− mice decreased germinal center B cell numbers and antigen-specific immunoglobulin concentrations. Together, these data indicate an inhibitory role of PU.1 in the function of T follicular helper cells, germinal centers, and Tfh-dependent humoral immunity.
doi:10.4049/jimmunol.1500780
PMCID: PMC4592843  PMID: 26363052
16.  Altered STAT4 isoform expression in patients with inflammatory bowel disease 
Inflammatory bowel diseases  2015;21(10):2383-2392.
BACKGROUND & AIMS
Crohn’s disease (CD) and ulcerative colitis (UC) are major forms of inflammatory bowel disease (IBD) and pathogenesis involves a complex interplay between genetic, environmental and immunological factors. We evaluated isoform expression of the IL-12-activated transcription factor STAT4 in children with CD and UC.
METHODS
We performed a study where we collected biopsy samples from both newly diagnosed CD and UC patients. We further collected blood samples from newly diagnosed CD and UC patients as well as patients who had a flare-up after being in clinical remission, and examined the ratios of STAT4β/STAT4α mRNA. In addition to STAT4 isoforms we measured the expression of the cytokines TNFα, IFNγ, GM-CSF and IL-17 using PCR of biopsy samples and multiplex analysis of patient serum samples.
RESULTS
Ratios of STAT4β/STAT4α were increased in specific GI tract segments in both CD and UC patients that correlate with location and severity of inflammation. In contrast, we did not observe changes in STAT4β/STAT4α ratios in biopsy specimens from eosinophilic esophagitis patients. We also observed increased STAT4β/STAT4α ratios in the peripheral blood mononuclear cells of UC and CD patients, compared to healthy controls. Ratios were normalized after patient treatment with steroids.
CONCLUSIONS
Collectively, these data indicate that STAT4 isoforms could be an important non-invasive biomarker in the diagnosis and treatment of IBD, and that expression of these isoforms might provide further insight into the pathogenesis of IBD.
doi:10.1097/MIB.0000000000000495
PMCID: PMC4567388  PMID: 26177303
STAT4 isoforms; IBD; biomarker
17.  New immunotherapies targeting the PD-1 pathway 
Ligands from the B7 family bind to receptors of the CD28 family, which regulate early T cell activation in lymphoid organs and control inflammation and autoimmunity in peripheral tissues. PD-1, a member of the CD28 family, is an inhibitory receptor on T cells and is responsible for their dysfunction in infectious diseases and cancers. The complex mechanisms controlling expression and signaling of PD-1 and PD-L1 are emerging. Recently completed and ongoing clinical trials that target these molecules have shown remarkable success by generating durable clinical responses in some cancer patients. In chronic viral infections, preclinical data reveal that targeting PD-1 and its ligands can improve T cell responses and viral clearance. There is also promise in stimulating this pathway for the treatment of autoimmune and inflammatory disorders.
doi:10.1016/j.tips.2015.06.005
PMCID: PMC4562806  PMID: 26162965
PD-1; PD-L1; PD-L2; immunotherapy; cancer; viral infection
18.  An Inhibitory Role for the Transcription Factor Stat3 in Controlling IL-4 and Bcl6 Expression in Follicular Helper T cells 
The transcription factor Bcl6 is required for the development of the follicular helper T (TFH) cells. Cytokines that activate Stat3 promote Bcl6 expression and TFH cell differentiation. Previous studies with an acute virus infection model showed that TFH cell differentiation was decreased but not blocked in the absence of Stat3. In this study, we further analyzed the role of Stat3 in TFH cells. In Peyer’s patches (PPs), we found that compared to wild-type, Stat3-deficient TFH cells developed at a 25% lower rate, and expressed increased IFNγ and IL-4. While PP germinal center B (GCB) cells developed at normal numbers with Stat3-deficient TFH cells, IgG1 class switching was greatly increased. Following immunization with Sheep Red Blood Cells (SRBC), splenic Stat3-deficient TFH cells developed at a slower rate than in control mice and splenic GCB cells were markedly decreased. Stat3-deficient TFH cells developed poorly in a competitive bone marrow chimera environment. Under all conditions tested, Stat3-deficient TFH cells over-expressed both IL-4 and Bcl6, a pattern specific for the TFH cell population. Finally, we found in vitro that repression of IL-4 expression in CD4 T cells by Bcl6 required Stat3 function. Our data indicate that Stat3 can repress the expression of Bcl6 and IL-4 in TFH cells, and that Stat3 regulates the ability of Bcl6 to repress target genes. Overall, we conclude that Stat3 is required to fine-tune the expression of multiple key genes in TFH cells, and that the specific immune environment determines the function of Stat3 in TFH cells.
doi:10.4049/jimmunol.1500335
PMCID: PMC4546859  PMID: 26188063
19.  Precipitating Circumstances of Suicide and Alcohol Intoxication among U.S. Ethnic Groups 
Background
To assess the prevalence of nine different types of precipitating circumstances among suicide decedents, and examine the association between circumstances and post-mortem blood alcohol content (BAC ≥ 0.08 g/dl.) across U.S. ethnic groups.
Methods
Data come from the restricted 2003-2011 National Violent Death Reporting System (NVDRS), with post-mortem information on 59,384 male and female suicide decedents for 17 states of the U.S.
Results
Among men, precipitating circumstances statistically associated with a BAC ≥ 0.08 g/dl were physical health and job problems for Blacks, and experiencing a crisis, physical health problems and intimate partner problem for Hispanics. Among women, the only precipitating circumstance associated with a BAC ≥ 0.08 g/dl was substance abuse problems other than alcohol for Blacks. The number of precipitating circumstances present before the suicide was negatively associated with a BAC ≥ 0.08 g/dl for Whites, Blacks and Hispanics.
Conclusions
Selected precipitating circumstances were associated with a BAC ≥ 0.08 g/dl, and the strongest determinant of this level of alcohol intoxication prior to suicide among all ethnic groups was the presence of an alcohol problem.
doi:10.1111/acer.12788
PMCID: PMC4515182  PMID: 26173709
alcohol; suicide; NVDRS; race/ethnicity; precipitating circumstances
20.  Th9 cells are required for tissue mast cell accumulation during allergic inflammation 
Background
IL-9 is important for the growth and survival of mast cells. IL-9 is produced by T cells, NKT cells, mast cells, eosinophils, and innate lymphoid cells, although the cells required for mast cell accumulation during allergic inflammation remain undefined.
Objective
To elucidate the role of Th9 cells in promoting mast cell accumulation in models of allergic lung inflammation.
Methods
Adoptive transfer of OVA-specific Th2 and Th9 cells was used to assess the ability of each subset to mediate mast cell accumulation in tissues. Mast cell accumulation was assessed in wild type mice and mice with PU.1-deficient T cells subjected to acute and chronic models of allergic inflammation.
Results
Adoptive transfer experiments demonstrated that recipients of Th9 cells had significantly higher mast cell accumulation and expression of mast cell proteases as compared to control or Th2 recipients. Mast cell accumulation was dependent on IL-9, but not IL-13, cytokine required for many aspects of allergic inflammation. In models of acute and chronic allergic inflammation, decreased IL-9 levels in mice with PU.1-deficient T cells corresponded to diminished tissue mast cell numbers and expression of mast cell proteases. Mice with PU.1-deficient T cells have defects in IL-9 production from CD4+ T cells, but not NKT cells or innate lymphoid cells, suggesting a T helper cell-dependent phenotype. Rag1−/− mice subjected to a chronic model of allergic inflammation displayed reduced mast cell infiltration comparable to accumulation in mice with PU.1-deficient T cells, emphasizing the importance of IL-9 produced by T cells in mast cell recruitment.
Conclusion
Th9 cells are a major source of IL-9 in models of allergic inflammation and play an important role in mast cell accumulation and activation.
doi:10.1016/j.jaci.2015.01.021
PMCID: PMC4530056  PMID: 25746972
Th9 cells; Th2 cells; mast cells; allergic inflammation; PU.1
21.  STAT6 and PARP Family Members in the Development of T Cell-dependent Allergic Inflammation 
Immune Network  2016;16(4):201-210.
Allergic inflammation requires the orchestration of altered gene expression in the target tissue and in the infiltrating immune cells. The transcription factor STAT6 is critical in activating cytokine gene expression and cytokine signaling both in the immune cells and in target tissue cells including airway epithelia, keratinocytes and esophageal epithelial cells. STAT6 is activated by the cytokines IL-4 and IL-13 to mediate the pathogenesis of allergic disorders such as asthma, atopic dermatitis, food allergy and eosinophilic esophagitis (EoE). In this review, we summarize the role of STAT6 in allergic diseases, its interaction with the co-factor PARP14 and the molecular mechanisms by which STAT6 and PARP14 regulate gene transcription.
doi:10.4110/in.2016.16.4.201
PMCID: PMC5002446  PMID: 27574499
STAT; PARP; Allergic inflammation; T cell
22.  CD4 T cells but not Th17 cells are Required for Mouse Lung Transplant Obliterative Bronchiolitis 
Lung transplant survival is limited by obliterative bronchiolitis (OB), but the mechanisms of OB development are unknown. Previous studies in a mouse model of orthotopic lung transplantation suggested a requirement for IL-17. We have used this orthotopic mouse model to investigate the source of IL-17A and the requirement for T cells producing IL-17A. The major sources of IL-17A were CD4+ T cells and γδ T cells. Depletion of CD4+ T cells led to a significantly decreased frequency and number of IL-17A+ lymphocytes and was sufficient to prevent acute rejection and OB. However, mice with STAT3-deficient T cells, which are unable to differentiate into Th17 cells, rejected lung allografts and developed OB similar to control mice. The frequency of IL-17A+ cells was not decreased in mice with STAT3-deficient T cells due mainly to the presence of IL-17A+ γδ T cells. Deficiency of γδ T cells also did not affect the development of airway fibrosis. Our data suggest that CD4+ T cells are required for OB development and expansion of IL-17A responses in the lung, while Th17 and γδ T cells are not absolutely required and may compensate for each other.
doi:10.1111/ajt.13215
PMCID: PMC4679154  PMID: 25773063
CD4; T-cells; lung transplantation; Th17 cells; STAT3; γδ T-cells
23.  Diverse inflammatory cytokines induce selectin ligand expression on murine CD4 T cells via p38 alpha MAP kinase1 
Selectins are glycan-binding adhesion molecules which mediate the initial steps of leukocyte recognition of endothelium. Cytokines control numerous aspects of CD4 T helper differentiation, but how cytokines control induction of ligands for E- and P-selectin on T helper subsets remains poorly understood. Among 20 cytokines that affect T helper cell differentiation, we identified six, IL-12, IL-18, IL-27, IL-9, IL-25 and TGFβ1, that induce expression of selectin ligands on murine CD4 T cells above the low levels associated with TCR engagement. Collectively, these six cytokines could potentially account for selectin ligand expression on all of the currently defined non-sessile T helper lineages, including Th1, Th2, Th9, Th17 and Treg. Induction of selectin ligand expression by each of these six cytokines was almost completely inhibited by pharmacologic inhibition of p38 MAPK, but not other MAPKs, or by conditional genetic deletion of p38 alpha MAPK. Analysis of the expression of key glycosyltransferase genes revealed that p38 alpha signaling was selectively required for induction of Fut7 and Gcnt1, but not for induction of St3gal4 or St3gal6. Constitutively active MKK6, an immediate upstream activator of p38 MAPK, induced selectin ligand expression equivalent to that of cytokines, and this induction was completely dependent on expression of p38 alpha. Our results identify the repertoire of cytokines responsible for selectin ligand induction on CD4 T cells and provide a mechanistic link between T helper development and T cell migration.
doi:10.4049/jimmunol.1500485
PMCID: PMC4698157  PMID: 25941329
24.  The Development and in vivo function of TH9 cells 
Nature reviews. Immunology  2015;15(5):295-307.
The specialized cytokine secretion profiles of T helper (TH) cells are the basis for a focused and efficient immune response. On the 20th anniversary of the first descriptions of cytokine signals that act to differentiate interleukin-9 (IL-9)-secreting T cells, this review focuses on the extracellular signals and transcription factors that promote the development of what we now term TH9 cells, which are characterized by the production of this cytokine. We summarize our current understanding of the contribution of TH9 cells to both effective immunity and immunopathological disease and propose that TH9 cells could be targeted for the treatment of allergic and autoimmune disease.
doi:10.1038/nri3824
PMCID: PMC4445728  PMID: 25848755
25.  Acute alcohol use among suicide decedents in 14 U.S. States: Impacts of off-premise and on-premise alcohol outlet density 
Addiction (Abingdon, England)  2014;110(2):300-307.
Background and Aims
This study estimates the association between per capita alcohol retail outlet density and blood alcohol concentration (BAC) from 51,547 suicide decedents. It also analyzes the relationship between alcohol outlet density and socio-demographic characteristics among alcohol positive suicide decedents in the United States by racial/ethnic groups and method of suicide.
Design
Analysis of U.S. data, 2003–11, National Violent Death Reporting System
Setting
Suicide decedents from 14 U.S. States
Cases
A total of 51,547 suicide decedents tested for blood alcohol content.
Measurements
Blood alcohol content and levels were derived from coroner/medical examiner reports. Densities of county level on-premise and off-premise alcohol retail outlets were calculated using the 2010 Census.
Findings
Multilevel logistic regression models suggested that higher off-premise alcohol outlet densities were associated with greater proportions of alcohol-related suicides among men -- for suicides with alcohol present (BAC>0; adjusted odds ratio [AOR]= 1.08, 95% confidence interval [CI]= 1.03–1.13). Interactions between outlet density and decedents’ characteristics were also tested. There was an interaction between off-premise alcohol availability and American Indian/Alaska Native race (AOR=1.36; 95% CI=1.10–1,69) such that this sub-group had highest BAC positivity. On-premise density was also associated with BAC > 0 (AOR=1.05; 95% CI=1.03–1.11) and BAC≥ 0.08 (AOR=1.05; 95% CI=1.02–1.09) among male decedents.
Conclusions
County-level on- and off-premise density are associated with alcohol-related suicide, especially among American Indians/Alaska Natives.
doi:10.1111/add.12762
PMCID: PMC4427246  PMID: 25310999
suicide; acute alcohol use; alcohol outlet density; U.S. States

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