Loss Of CD4 Research Articles

Dynamics of Cytokine/Chemokine Responses in Intestinal CD4+and CD8+T Cells during Acute Simian Immunodeficiency Virus Infection

Loss of intestinal CD4(+) T cells was associated with decreased production of several T-helper 1 (TH1) and TH2 cytokines and increased production of interleukin 17 (IL-17), gamma interferon (IFN-γ), CCL4, and granulocyte-macrophage colony-stimulating factor (GM-CSF) by CD8(+) T cells 21 days after simian immunodeficiency virus (SIV) infection in rhesus macaques. Shifting of mucosal TH1 to TH2 or T-cytotoxic 1 (TC1) to TC2 cytokine profiles was not evident. Additionally, both CD4(+) and CD8(+) T cells showed upregulation of macrophage migration inhibition factor (MIF) and basic fibroblast growth factor (FGF-basic) cytokines that have been linked to HIV disease progression.

Quantification of hepatic FOXP3+ T‐lymphocytes in HIV/hepatitis C coinfection

Coinfection with HIV adversely impacts every stage of hepatitis C (HCV) infection. Liver damage in HCV infection results from host antiviral responses rather than direct viral pathogenesis. Despite depressed cellular immunity, coinfected patients show accelerated hepatic fibrosis compared with HCV monoinfected patients. This paradox is poorly understood. T-regulatory (Treg) cells (CD4+ and FOXP3+) are hypothesized to limit hepatic damage in HCV. Our hypothesis was that reduced frequency of hepatic Treg in HIV/HCV coinfection compared with HCV monoinfection may explain poorer outcomes. We quantified FOXP3+, CD4+, CD8+ and CD20+ cells in liver biopsies of 35 male subjects matched by age and ISHAK fibrosis score, 12 HIV monoinfected, 11 HCV monoinfected and 12 HIV/HCV coinfected. Cell counts were performed using indirect immunohistochemical staining and light microscopy. HIV/HCV coinfected subjects had fewer hepatic FOXP3+ (P=0.031) and CD4+ cells (P=0.001) than HCV monoinfected subjects. Coinfected subjects had more hepatic CD8+ cells compared with HCV monoinfected (P=0.023), and a lower ratio of FOXP3+ to CD8+ cells (0.08 vs 0.27, P<0.001). Multivariate analysis showed number of CD4+ cells controlled for differences in number of FOXP3+ cells. Fewer hepatic FOXP3+ and CD4+ cells in HIV/HCV coinfection compared with HCV monoinfection suggests lower Treg activity, driven by an overall loss of CD4+ cells. Higher number of CD8+ cells in HIV/HCV coinfection suggests higher cytotoxic activity. This may explain poorer outcomes in HIV/HCV coinfected patients and suggests a potential mechanism by which highly active antiretroviral therapy may benefit these patients.

Peripheral T-cell lymphoma emerging in a patient with aggressive polymyositis: molecular evidence for neoplastic transformation of an oligoclonal T-cell infiltrate

We report a rare case of peripheral T-cell lymphoma arising in a 52-year-old man with biopsy-proven aggressive polymyositis, who had cardiac involvement, progressive bulbar symptoms, and died 11months post diagnosis due to multiorgan failure. Using a multimodality approach including immunohistochemistry, genome-wide single nucleotide polymorphism (SNP)-array analysis, and high-throughput sequencing of the complementary determining region 3 (CDR3) of T-cell receptor beta (TCRβ) genes, our study demonstrates a molecular link between polymyositis and T-cell lymphoma, and provides evidence of the rapid and possibly late occurrence of genomic instability during neoplastic transformation of an oligoclonal T-cell population. Immunohistochemical analysis revealed loss of CD5, CD7, and CD8 antigen expression in autopsy tissue samples, as well as the occurrence of aberrant CD56 expression, not seen in pre-mortem biopsies, supporting the emergence of a neoplastic T-cell population. Multiplex polymerase chain reaction and next-generation sequencing of the TCRβ CDR3 region displayed two unique T-cell clones in both the diagnostic biopsy confirming polymyositis and the autopsy muscle tissue exhibiting T-cell lymphoma, linking the two pathological processes. SNP-array analysis revealed complex genomic abnormalities at autopsy but not in the pre-mortem muscle biopsies displaying polymyositis, confirming malignant transformation of the oligoclonal T-cell infiltrate. Our findings raise the possibility that clinically aggressive polymyositis might represent a preneoplastic condition in some instances, similar to certain other autoimmune and inflammatory disorders.

CD3−NK1.1+ cells aid in the early induction of a Th1 response to an attaching and effacing enteric pathogen

Extracellular attaching and effacing (A/E) pathogens including pathogenic Escherichia coli colonize the host gut causing diarrhea and inflammation. Although much is known regarding the pathogenesis of A/E bacteria, there remains an incomplete understanding of host immune responses to these microbes. NK cells are an important source of IFN-γ and are essential for early innate responses to viral pathogens; however, their role during extracellular bacterial infections is still largely unexplored. We studied the host response to the murine A/E pathogen Citrobacter rodentium to investigate NK-cell function during infection. NK1.1⁺ cell depletions and analysis of colonic intestinal inflammation following Citrobacter infection demonstrated that CD3⁻NK1.1⁺ cells play an important role in the initial clearance of C. rodentium, as evidenced by higher bacterial load, intestinal pathology, and crypt hyperplasia at the peak of inflammation in depleted mice. Loss of CD3⁻NK1.1⁺ cells resulted in lower colonic IFN-γ, TNF-α, and IL-12, and a delay in homing of IFN-γ⁺CD4⁺ T cells to the gut. Loss of this response resulted in lower anti-C. rodentium IgG in NK1.1-depleted mice. These data establish that CD3⁻NK1.1⁺ cells are critical for inducing an early Th1 response involved in clearance of a pathogen that is restricted to the gastrointestinal tract.

Multifunctional Double-negative T Cells in Sooty Mangabeys Mediate T-helper Functions Irrespective of SIV Infection

Studying SIV infection of natural host monkey species, such as sooty mangabeys, has provided insights into the immune changes associated with these nonprogressive infections. Mangabeys maintain immune health despite high viremia or the dramatic CD4 T cell depletion that can occur following multitropic SIV infection. Here we evaluate double-negative (DN)(CD3+CD4−CD8−) T cells that are resistant to SIV infection due to a lack of CD4 surface expression, for their potential to fulfill a role as helper T cells. We first determined that DN T cells are polyclonal and predominantly exhibit an effector memory phenotype (CD95+CD62L−). Microarray analysis of TCR (anti-CD3/CD28) stimulated DN T cells indicated that these cells are multifunctional and upregulate genes with marked similarity to CD4 T cells, such as immune genes associated with Th1 (IFNγ), Th2 (IL4, IL5, IL13, CD40L), Th17 (IL17, IL22) and TFH (IL21, ICOS, IL6) function, chemokines such as CXCL9 and CXCL10 and transcription factors known to be actively regulated in CD4 T cells. Multifunctional T-helper cell responses were maintained in DN T cells from uninfected and SIV infected mangabeys and persisted in mangabeys exhibiting SIV mediated CD4 loss. Interestingly, TCR stimulation of DN T cells from SIV infected mangabeys results in a decreased upregulation of IFNγ and increased IL5 and IL13 expression compared to uninfected mangabeys. Evaluation of proliferative capacity of DN T cells in vivo (BrDU labeling) indicated that these cells maintain their ability to proliferate despite SIV infection, and express the homeostatic cytokine receptors CD25 (IL2 receptor) and CD127 (IL7 receptor). This study identifies the potential for a CD4-negative T cell subset that is refractory to SIV infection to perform T-helper functions in mangabeys and suggests that immune therapeutics designed to increase DN T cell function during HIV infection may have beneficial effects for the host immune system.

Galectin-9 and IL-21 Mediate Cross-regulation between Th17 and Treg Cells during Acute Hepatitis C

Loss of CD4 T cell help correlates with virus persistence during acute hepatitis C virus (HCV) infection, but the underlying mechanism(s) remain unknown. We developed a combined proliferation/intracellular cytokine staining assay to monitor expansion of HCV-specific CD4 T cells and helper cytokines expression patterns during acute infections with different outcomes. We demonstrate that acute resolving HCV is characterized by strong Th1/Th17 responses with specific expansion of IL-21-producing CD4 T cells and increased IL-21 levels in plasma. In contrast, viral persistence was associated with lower frequencies of IL-21-producing CD4 T cells, reduced proliferation and increased expression of the inhibitory receptors T cell immunoglobulin and mucin-domain-containing-molecule-3 (Tim-3), programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) on HCV-specific CD8 T cells. Progression to persistent infection was accompanied by increased plasma levels of the Tim-3 ligand Galectin-9 (Gal-9) and expansion of Gal-9 expressing regulatory T cells (Tregs). In vitro supplementation of Tim-3high HCV-specific CD8 T cells with IL-21 enhanced their proliferation and prevented Gal-9 induced apoptosis. siRNA-mediated knockdown of Gal-9 in Treg cells rescued IL-21 production by HCV-specific CD4 T cells. We propose that failure of CD4 T cell help during acute HCV is partially due to an imbalance between Th17 and Treg cells whereby exhaustion of both CD4 and CD8 T cells through the Tim-3/Gal-9 pathway may be limited by IL-21 producing Th17 cells or enhanced by Gal-9 producing Tregs.

STAT4-Dependent and -Independent Th2 Responses Correlate with Protective Immunity against Lung Infection with Pneumocystis murina

Although it is clear that the loss of CD4(+) T cells is a predisposing factor for the development of Pneumocystis pneumonia, specific Th mechanisms mediating protection are not well understood. Th1, Th2, and Th17 responses have each been implicated in protective responses during infection. As STAT4 may promote Th1 and Th17 development, yet antagonize Th2 development, we investigated its role in Pneumocystis murina host defense. STAT4 was required for Th1 and, unexpectedly, Th2 responses in the lungs of C57BL/6 (BL/6) and BALB/c mice 14 d postchallenge, but only BALB/c Stat4(-/-) mice demonstrated susceptibility to P. murina lung infection. BL/6 Stat4(-/-), but not BALB/c Stat4(-/-), mice maintained an enhanced alternatively activated (M2) macrophage signature in the lungs, which we have previously reported to be associated with enhanced P. murina clearance. In addition, anti-P. murina class-switched Abs were increased in BL/6 Stat4(-/-) mice, but not BALB/c Stat4(-/-) mice. Supporting our experimental observations, plasma from HIV-infected individuals colonized with Pneumocystis jirovecii contained significantly lower levels of the Th2 cytokines IL-4, IL-5, and IL-13 compared with HIV-infected individuals who were not colonized. Collectively, our data suggest that robust local and systemic Th2-mediated responses are critical for immunity to Pneumocystis.

AB0052 Polymyalgia rheumatica is characterized by pro-inflammatory, senescent CD8+ T cells

BackgroundPolymyalgia rheumatica (PMR) is a frequent, inflammatory rheumatic disease affecting elderly people. Previous studies suggest that T cell mediated immune responses contribute to PMR. However, little is known about CD4+...

Strategies for Relapsed Peripheral T-Cell Lymphoma: The Tail That Wags the Curve

A 69-year-old woman was referred for further evaluation and management of relapsed angioimmunoblastic T-cell lymphoma. At diagnosis, she received six cycles of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and achieved a complete response (CR). Her first surveillance computed tomography scan 3 months later demonstrated enlarging cervical lymphadenopathy. A lymph node excision confirmed relapsed angioimmunoblastic T-cell lymphoma with atypical lymphocytes expressing CD3, CD4, CD10, PD-1, and EBER, with loss of CD5 (Fig 1). A clonal T-cell receptor beta and gamma rearrangement by polymerase chain reaction was identical to that in her initial diagnostic biopsy. At our initial consultation, options for standard as well as investigational therapies were discussed, and HLA typing was initiated. The patient was enrolled onto an investigational phase II study; however, she developed progressive disease after two cycles. She was then treated with romidepsin 14 mg/m(2) administered intravenously for 3 consecutive weeks with 1 week off. After two cycles, she achieved a partial response, and after four additional cycles, she maintained her response without further improvement. We discussed additional treatment options.

A first-in-human (FIH) dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous BAL101553, a novel microtubule inhibitor, in adult patients with advanced solid tumors.

2566 Background: BAL101553, a pro-drug of the small molecule BAL27862, is a novel microtubule targeting agent (MTA) with cytotoxic and vascular disrupting properties. Pre-clinical data showed anti-proliferative activity in several in vitro and xenograft tumour models, including tumours refractory to conventional MTAs through diverse resistance mechanisms. Primary objectives of this FIH study were determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included the evaluation of PK, PD and anti-tumour activity. Methods: An accelerated titration dose-escalation design was used. Eligible patients (pts) with advanced solid tumours, who had failed standard therapy, received BAL101553 as a 2-h intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Adverse events (AEs) were assessed according to CTCAEv4. Disease response was assessed by RECIST 1.1 every 2 cycles. Results: 16 pts (7 male; median age 52 years; range 29-80) with solid tumours were treated at 4 dose levels (15, 30, 45 and 60 mg/m2). DLTs were observed at 60 mg/m2 and included rapidly reversible grade (G) 3 hypertension (HTN) and G3 reduced mobility/ dizziness. DLT criteria for HTN were subsequently modified. Frequent drug-related AEs were injection site reactions, nausea, vomiting (all G1-2), and G2-3 HTN (transient during the infusion; responding to nifedipine). One pt experienced G2 peripheral neuropathy at 60 mg/m2. PK analyses indicated conversion of BAL101553 to the active BAL27862, dose proportional exposure for both compounds and a half-life of BAL27862 in a range of 11 to 27 h. Preliminary tumour PD data comparing pre/post biopsies showed loss of CD34+ capillaries and focally decreased proliferation. A confirmed partial response was demonstrated in 1 pt with ampullary (pancreaticobiliary) cancer maintained on treatment for &gt;16 cycles with intra-pt dose escalation. 2 pts (laryngeal and rectal cancer) demonstrated stable disease &gt;16 weeks. Conclusions: BAL101553 is well tolerated up to 60 mg/m2 with evidence of anti-tumour activity. Dose escalation continues to determine the MTD. Clinical trial information: NCT01397929.

High intrapatient HIV-1 evolutionary rate is associated with CCR5-to-CXCR4 coreceptor switch

In approximately 70% of individuals infected with HIV-1 subtype B, the virus switches coreceptor use from exclusively CCR5 use (R5 virus) to either inclusion of or exclusively CXCR4 use (X4 virus) during infection. This switch is associated with an accelerated loss of CD4+ T-cells and a faster progression to AIDS. Despite intensive research, the mechanisms responsible for coreceptor switch remains elusive. In the present study, we investigated associations between viral evolutionary rate and selection pressure versus viral coreceptor use and rate of disease progression in eight patients with longitudinally sampled HIV-1 env V1–V3 sequences. By employing a Bayesian hierarchical phylogenetic model, we found that the HIV-1 evolutionary rate was more strongly associated with coreceptor switch than with rate of disease progression in terms of CD4+T-cell decline. Phylogenetic analyses showed that X4 variants evolved from R5 populations. In addition, coreceptor switch was associated with higher evolutionary rates on both the synonymous and non-synonymous substitution level, but not with dN/dS ratio rates. Our findings suggest that X4 viruses evolved from pre-existing R5 viral populations and that the evolution of coreceptor switch is governed by high replication rates rather than by selective pressure. Furthermore, the association of viral evolutionary rate was more strongly associated with coreceptor switch than disease progression. This adds to the understanding of the complex virus–host interplay that influences the evolutionary dynamics of HIV-1 coreceptor use.

Impaired CD4+ T cell stimulation of NK cell anti-fibrotic activity may contribute to accelerated liver fibrosis progression in HIV/HCV patients

HIV/HCV co-infection is characterized by a faster progression to liver fibrosis compared to HCV mono-infection. Epidemiologic studies found an association between low CD4(+) T cell counts and advanced stages of liver fibrosis. However, the mechanisms underlying this association remain unclear. CD4(+) T cells critically modulate NK cell activity. Of note, NK cells have been shown to display anti-fibrotic activity via killing of activated hepatic stellate cells (HSC). Thus, we speculated that CD4(+) T cells might modulate fibrosis progression by interacting with NK cells. NK cells from HCV(+) (n=35), HIV(+)/HCV(+) (n=28), HIV(+) (n=8) patients, and healthy controls (n=30) were used in this study. NK cells were cultured in the presence or absence of supernatants from CD3/CD28-stimulated CD4(+) cells. Then, NK cells were co-incubated with activated HSC and studied for degranulation, IFN-γ secretion, and induction of HSC apoptosis. Following incubation with CD4(+) T cell supernatants, NK cells displayed a significantly increased activity against primary HSC as compared to unstimulated NK cells. This effect was, at least in part, mediated via an IL-2 dependent upregulation of NKG2D expression. HCV/HIV co-infection was associated with an impaired IL-2 secretion of CD4(+) T cells resulting in an ineffective stimulation of anti-fibrotic NK cell function. Here, we show that CD4(+) T cells are able to stimulate anti-fibrotic NK cell activity via IL-2 mediated upregulation of NKG2D. HIV-induced loss of CD4(+) T cells together with an impaired activity of CD4(+) T cells may contribute to accelerate progression of liver fibrosis observed in co-infection.

Upregulation of RCAN1 causes Down syndrome-like immune dysfunction

BackgroundPeople with Down syndrome (DS) are more susceptible to infections and autoimmune disease, but the molecular genetic basis for these immune defects remains undetermined. In this study, we tested whether...

MTOR-dependent regulation of mucosal CD8 T cell immunity (P3221)

Abstract Mucosal tissues are sites of frequent pathogen exposure and major routes for the transmission of infectious diseases. Migration of virus-specific memory CD8 T cells into mucosal tissues such as the small intestine and vaginal mucosa is highly restricted to non-circulating tissue resident memory CD8 T cells. Resident mucosal memory CD8 T cells are sufficient to protect against the establishment of mucosa-acquired viral infections, and thus it is essential to develop vaccine strategies that elicit long-lived mucosal CD8 T cells. CD8 T cells residing in mucosal tissues are phenotypically distinct from those in secondary lymphoid tissues and factors critical for their formation are poorly defined. It is also unclear whether mucosal CD8 T cells possess a unique requirement for their generation and maintenance from that of circulating memory CD8 T cells. We report that unlike in the secondary lymphoid tissues, the formation of virus-specific memory CD8 T cells in the small intestine and vaginal mucosa is dependent on mTOR signaling. In addition, we demonstrate using a CD8 T cell mediated model of intestinal autoimmune disease that inhibiting mTOR results in a loss of CD8 T cells in the small intestine and protects mice from lethality. Furthermore, we will discuss data that targets mTOR signaling intrinsically within the CD8 T cells to provide mechanistic insight into how the mTOR pathway specifically controls the generation of mucosal CD8 T cells in response to viral infections.

STAT4-dependent and -independent T helper type-2 immunity mediates protection against Pneumocystis lung infection (P3304)

Abstract Although it is clear that the loss of CD4+ T cells is a predisposing factor for the development of Pneumocystis pneumonia, the protective mechanisms mediated by CD4+ T cells are not well understood. Augmented production of Th1-type cytokines in the lungs of IL-10-/- mice correlated with enhanced P. murina clearance, whereas neutralization of IL-17 in normal mice compromised fungal clearance, suggesting that Th1 and Th17 cells play an important role during infection. STAT4 is critical for optimal Th1 and Th17 development, therefore we investigated its role in P. murina host defense. Our data shows that STAT4 was required for Th1 and, unexpectedly, Th2 responses in the lungs of C57BL/6 (BL/6) and Balb/c mice 14 days after infection, but only Balb/c STAT4-/- mice were susceptible to P. murina infection. Th2 responses in the lungs of BL/6 STAT4-/- mice, but not Balb/c STAT4-/- mice, were intact 28 days after infection and correlated with elevated M2 macrophage polarization. Additionally, anti-P. murina class-switched antibodies were increased in BL/6 STAT4-/- mice, but not Balb/c STAT4-/- mice, as a result of hyper-Th2 responses in the draining lymph nodes. Supporting our experimental observations, we found that lower IL-4, IL-5 and IL-13 levels in plasma from HIV+ patients correlated with Pneumocystis colonization. Collectively, our data suggests that robust local and systemic Th2-mediated responses are critical for immunity to Pneumocystis.

Differential role of Bcl-2 in CD8+ and CD4+ T cell homeostasis (P1336)

Abstract Regulated induction of apoptosis is critical for normal functioning of the adaptive immune system. Both TCR/MHC interactions and by soluble cytokines maintain T cells via their ability to modulate Bcl-2 family members, although the dependence of CD4+ and CD8+ T cells upon individual anti-apoptotic molecules remains unclear. Here, we used mice with a conditional allele of Bcl-2 crossed with dLck-Cre mice to assess the role of Bcl-2 in CD4+ and CD8+ T cell survival. We found that dlck-Cre-driven deletion of Bcl-2 resulted in a massive loss of naïve CD8+ T cells, but only a modest loss of naïve CD4+ T cells. We next tested if Bcl-2 was important for effector CD4+ T cell survival after infection with lymphocytic choriomeningitis virus (LCMV). Interestingly, the majority of LCMV-specific CD4+ T cells did not require Bcl-2 to survive contraction of the response. Further, treatment of mice with ABT-737, a Bcl-2, Bcl-xL, and Bcl-w inhibitor, only modestly increased the loss of effector CD4+ T cells, suggesting that neither Bcl-2, Bcl-xL, nor Bcl-w are required for survival of effector CD4+ T cells. Instead, we find that the Bcl-2 family member, A1 is increased in effector CD4+ T cells and we are currently investigating the role of A1 in the survival of naïve and activated CD4+ T cells. As the pro-apoptotic Bcl-2 family member Bim is critical to control naïve and effector CD4+ T cells, A1 may be an important Bim antagonist that promotes effector CD4+ T cell responses.

B cells shape T cell responses during Pneumocystis infection (P3053)

Abstract Pneumocystis pneumonia (PCP) remains one of the leading causes of death in immunocompromised patients. Disease is attributed to the loss of CD4 T cells; however recent studies suggest that B cells also play a protective role in clearing PC in an Ig-independent manner through antigen presentation. Several patients treated with anti-CD20 have developed PCP and thus we investigated the effect of anti-CD20 on primary PC infection. We hypothesized that B cells in part function as a critical antigen-presenting cell to helper T cells. To test this, C57BL/6 WT mice were administered anti-CD20, anti-CD4 (as a pos. control) or both, and then infected with a 105 inoculum of Pneumocystis murina. Lung mononuclear cells were harvested two weeks after infection, assessed for cellularity and then stimulated in vitro with PC antigen for cytokine profiling. Even though CD20-depleted animals had unaltered T cells numbers, there were diminished cytokine responses for IL-5, IL-17, and IL-10. These data suggest that B cells are involved in mediating optimal T cell cytokine responses against PC. We are currently testing if B cells are required in the recall responses from memory T cells by performing B cell depletion during the re-challenge of mice that have recovered from primary PC infection. We are also investigating if B cells modify T regulatory cells during Immune Reconstitution Inflammatory Syndrome (IRIS), a disease that affects a subset of patients upon reconstitution of CD4+ cells.

TCF-1 and LEF-1 promote CD4+ T cell lineage choice by upregulating Myb (P4439)

Abstract During late stages of T cell development, positively selected CD4+CD8+ (DP) thymocytes must make a lineage choice decision to become MHC-I-restricted cytotoxic CD8+ T cells or MHC-II-restricted helper CD4+ T cells. This lineage choice process is determined by extrinsic signals such as TCR and γc cytokines and by intrinsic transcriptional factors such as Myb, Gata3, ThPOK and Runx. The canonical Wnt effector transcription factors, TCF-1 and LEF-1, are essential for the transition from CD4-CD8- (DN) to the DP stage, but their requirement beyond the DP stage is unknown. Here we show that deficiency in TCF-1 resulted in a preferential loss of CD4+ T cells and reduced CD4/CD8 ratio, and this phenotype was exacerbated upon loss of both TCF-1 and LEF-1. By crossing TCF-1-/- mice to MHC-I-deficient strain or OT-2 CD4+ TCR transgenic strain, we found that DP thymocytes selected on MHC-II were re-directed to the CD8 lineage in the absence of TCF-1 and/or LEF-1. Mechanistically, we observed that Myb expression is greatly diminished in post-select DP thymocytes lacking TCF-1 and/or LEF-1, and that activation of the Wnt signaling pathway in post-select DP thymocytes induced Myb expression. Collectively, these findings revealed a novel role of Wnt effectors TCF-1 and LEF-1 in promoting CD4+ lineage choice, which is likely mediated by Wnt-dependent upregulation of Myb.

Mcl-1 antagonizes Bax/Bak to promote effector CD4(+) and CD8(+) T-cell responses.

Members of the Bcl-2 family have critical roles in regulating tissue homeostasis by modulating apoptosis. Anti-apoptotic molecules physically interact and restrain pro-apoptotic family members preventing the induction of cell death. However, the specificity of the functional interactions between pro- and anti-apoptotic Bcl-2 family members remains unclear. The pro-apoptotic Bcl-2 family member Bcl-2 interacting mediator of death (Bim) has a critical role in promoting the death of activated, effector T cells following viral infections. Although Bcl-2 is an important Bim antagonist in effector T cells, and Bcl-xL is not required for effector T-cell survival, the roles of other anti-apoptotic Bcl-2 family members remain unclear. Here, we investigated the role of myeloid cell leukemia sequence 1 (Mcl-1) in regulating effector T-cell responses in vivo. We found, at the peak of the response to lymphocytic choriomeningitis virus (LCMV) infection, that Mcl-1 expression was increased in activated CD4(+) and CD8(+) T cells. Retroviral overexpression of Mcl-1-protected activated T cells from death, whereas deletion of Mcl-1 during the course of infection led to a massive loss of LCMV-specific CD4(+) and CD8(+) T cells. Interestingly, the co-deletion of Bim failed to prevent the loss of Mcl-1-deficient T cells. Furthermore, lck-driven overexpression of a Bcl-xL transgene only partially rescued Mcl-1-deficient effector T cells suggesting a lack of redundancy between the family members. In contrast, additional loss of Bax and Bak completely rescued Mcl-1-deficient effector T-cell number and function, without enhancing T-cell proliferation. These data suggest that Mcl-1 is critical for promoting effector T-cell responses, but does so by combating pro-apoptotic molecules beyond Bim.

Mucosal immunity in human and simian immunodeficiency lentivirus infections.

Overwhelming evidence indicates that distinct pathological phenomenon occurs within the gastrointestinal (GI) tract of progressively simian immunodeficiency virus (SIV)-infected Asian macaques and HIV-infected humans compared with other anatomical sites. Massive loss of GI tract lamina propria CD4 T cells, alteration in the profile of lymphocytic cytokine production, changes in the landscape of GI tract antigen-presenting cells, and variations to the structural barrier of the GI tract are hallmarks of progressive HIV/SIV infections. The pathology within the GI tract results in translocation of microbial products from the lumen of the intestine into peripheral circulation. These translocated microbial products directly stimulate the immune system and exacerbate immune activation and, thus, disease progression. Initiation of combination antiretroviral therapy (cART) does not restore completely the immunological abnormalities within the GI tract. This incomplete restoration within the GI tract may contribute to the increased mortality observed within HIV-infected individuals treated for decades with cART. Novel therapeutic interventions aimed at enhancing GI tract anatomy and physiology may improve the prognosis of HIV-infected individuals.