Regulating T-cell Survival Research Articles

Deletion of MyD88 in T‐Cells Worsens Cardiac Pathology Through Enhanced T‐Cell Survival and Induction of Cardiac Fibrosis

Heart failure (HF) is a leading cause of death worldwide, associated with cardiac and systemic inflammation. However, no anti‐inflammatory therapies have shown success. Damage associated molecular patterns (DAMPs) released in the heart activate myeloid cells through the adaptor “Myeloid differentiation primary response 88” (MyD88). This signaling cascade promotes cardiac antigen presentation to activate helper T‐cells. Once activated, T‐cells then infiltrate the heart and bind to VCAM‐1 on cardiac fibroblasts, (CFB), transforming them to myofibroblasts which coordinate cardiac fibrosis. MyD88 is also expressed in T‐cells, yet whether it is pro or anti‐inflammatory is less explored, and evidence suggests is context dependent. To investigate the role of T‐cell MyD88 in HF, we reconstituted Tcra‐/‐ mice, normally protected from HF induced by transaortic constriction (TAC), with WT or Myd88‐/‐ Type 1 helper T‐cells (Th1) in the onset of TAC. Surprisingly, we found that mice receiving Myd88‐/‐ Th1 cells showed increased cardiac T‐cells and fibrosis compared to mice receiving WT cells. We hypothesized that T‐cell MyD88 regulates cardiac T‐cell recruitment and survival, and as a result subsequent cardiac fibrosis. We found that Myd88‐/‐ Th1 cells exhibited increased survival in vitro determined by real time imaging of propidium iodide incorporation, as well as in vivo by performing competitive survival studies in which Tcra‐/‐ mice received equal WT CD45.1 Th1 cells and Myd88‐/‐ CD45.2 Th1 cells. Myd88‐/‐ Th1 cells also induced higher CFB α‐smooth muscle actin staining when cultured together, as well as bound more frequently to CFB and immobilized VCAM‐1. Together these data demonstrate that MyD88 limits T‐cell mediated cardiac fibrosis by regulating T‐cell survival, as well as by dampening T‐cell/fibroblast interactions. We identify novel role for T‐cell MyD88 in cardiac inflammation that may be modulated in HF.

The deficiency of Gαq leads to enhanced T-cell survival.

We have previously reported that Gαq, the α subunit of the Gq protein, had important roles in dendritic cell migration, B-cell survival and autoimmunity. In this study, we showed that the deficiency of Gαq led to enhanced T-cell survival. Cultured Gnaq(-/-) T cells exhibited survival advantages both in medium alone and in the presence of anti-CD3 stimulation. Gnaq(-/-) T cells still exhibited a survival advantage when they were cultured in the presence of interleukin (IL)-2 or IL-7. Gnaq(-/-) T cells were more resistant to activation-induced cell death (AICD) in vitro. The survival advantage of Gnaq(-/-) T cells was further confirmed by transferring T cells into syngeneic hosts in vivo. Gαq deficiency might promote T-cell survival by upregulated Bcl-xL expression and downregulated Fas and FasL expressions. Furthermore, upon T-cell receptor (TCR) ligation, Akt activity was increased in Gnaq(-/-) T cells in comparison with wild-type (WT) T cells. The survival advantage of Gnaq(-/-) T cells was significantly attenuated after adding Akt inhibitor. Taken together, our data demonstrated a negative role of Gαq in regulating T-cell survival.

Histone Deacetylase 6 (HDAC6) Influences T-Cell Activation and Survival: Implications For Cancer Immunotherapy

The role of histone deacetylases (HDACs) as epigenetic regulators of immune function is becoming increasingly clear. Recently, the role of specific HDACs in orchestrating T-cell maturation, survival and function has begun to emerge, giving rationale to selective therapy to direct immune responses in different disease settings, including cancer. In particular, HDAC6 has recently been characterized as a negative regulator of regulatory T-cell suppressive activity (de Zoeten, Molecular and Cellular Biology, 2011). Here we report an expanded, novel role of HDAC6 in regulating T-cell survival and activation. First, the relative expression of the eleven classic HDACs was evaluated in resting and activated T-cells from mouse and human samples. It was found that the majority of HDACs decrease in expression following activation, including HDAC6. Next, in a HDAC6KO mouse model, it was found that T-cells lacking HDAC6 had skewed survival when compared to wild-type murine T-cells. This difference seems to be the result of an increased CD4+ T-cells population in the lymph nodes, with a concomitant decrease in viable CD8+ T-cells. To determine whether this population skewing was the consequence of defects in HDAC6KO mice T-cell development, wild-type murine T-cells were treated with an isotype-selective HDAC6 inhibitor. The results seen in HDAC6KO T-cells were recapitulated when wild-type T-cells were activated and treated with HDAC6 specific inhibitors, indicating a role of HDAC6 outside of thymic development in promoting CD4+ T-cell survival at the expense of CD8+ T-cells. Interestingly, it was found that activated CD4+ T-cells displayed decreased expression of the apoptosis signaling receptor FAS after HDAC6 inhibition while no differences were observed in CD8+ T-cells under the same conditions. In addition to these results implicating HDAC6 in regulating T-cell survival, expression of surface markers was altered in both CD8+ and CD4+ T-cells, including enhanced expression of the activation molecule CD69 in stimulated T-cells treated with an isotype-selective HDAC6 inhibitor. Finally, in vivo studies in tumor-bearing HDAC6KO mice revealed a significantly delayed in tumor progression. Similar results were observed in lymphoma-bearing mice treated with HDAC6 specific inhibitors. Taken together, this data shows that HDACs are dynamic in expression with regards to T-cell activation state. More specifically, we have unveiled hereto-unexplored roles of HDAC6 in regulating T-cell survival and function, pointing at this specific HDAC as an appealing target to harness T-cell immunity in hematologic malignancies. Disclosures:No relevant conflicts of interest to declare.

Gimap3 and Gimap5 cooperate to maintain T‐cell numbers in the mouse

Gimap3 (IAN4) and Gimap5 (IAN5) are highly homologous GTP-binding proteins of the Gimap family. Gimap3 and Gimap5, whose transcripts are abundant in mature lymphocytes, can associate with antiapoptotic Bcl-2 family proteins. While it is established that Gimap5 regulates T-cell survival, the in vivo role of Gimap3 is unclear. Here we report the preparation and characteristics of mouse strains lacking Gimap3 and/or Gimap5. We found that the number of T cells was markedly reduced in mice deficient in both Gimap3 and Gimap5. The defects in T-cell cellularity were more severe in mice lacking both Gimap3 and Gimap5 than in mice lacking only Gimap5. No defects in the cellularity of T cells were detected in mice lacking only Gimap3, whereas bone marrow cells from Gimap3-deficient mice showed reduced T-cell production in a competitive hematopoietic environment. Moreover, retroviral overexpression and short hairpin RNAs-mediated silencing of Gimap3 in bone marrow cells elevated and reduced, respectively, the number of T cells produced in irradiated mice. These results suggest that Gimap3 is a regulator of T-cell numbers in the mouse and that multiple Gimap family proteins cooperate to maintain T-cell survival.

BAFF maintains T-cell survival by inducing OPN expression in B cells

Dysregulation of T-cell survival and apoptosis is the common cause of autoimmune diseases such as multiple sclerosis (MS). However, the factors inducing imbalance of T-cell survival and apoptosis in MS remains unclear. Here, we show that the resistance to apoptosis was associated with high levels of B-cell activating factor (BAFF). Blockade of BAFF with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor)-IgG significantly reduced T-cell survival in myelin oligodendroglia glycoprotein (MOG)-induced chronic experimental allergic encephalitis (EAE). Furthermore, BAFF induced anti-apoptotic molecule Bcl2 expression in T cells by up-regulating osteopontin (OPN) secretion from B cells. BAFF mainly induced OPN expression in splenic CD21−CD23+ B cells via a NF-kB dependent signaling pathway. In addition, we found that BAFF and OPN levels were increased in MS patients similar to the results obtained from our mice research. The study suggests that BAFF regulates T-cell survival by inducing OPN secretion in B cells in autoimmune diseases.

PPARγAgonists in Adaptive Immunity: What Do Immune Disorders and Their Models Have to Tell Us?

Adaptive immunity has evolved as a very powerful and highly specialized tool of host defense. Its classical protagonists are lymphocytes of the T- and B-cell lineage. Cytokines and chemokines play a key role as effector mechanisms of the adaptive immunity. Some autoimmune and inflammatory diseases are caused by disturbance of the adaptive immune system. Recent advances in understanding the pathogenesis of autoimmune diseases have led to research on new molecular and therapeutic targets. PPARγ are members of the nuclear receptor superfamily and are transcription factors involved in lipid metabolism as well as innate and adaptive immunity. PPARγ is activated by synthetic and endogenous ligands. Previous studies have shown that PPAR agonists regulate T-cell survival, activation and T helper cell differentiation into effector subsets: Th1, Th2, Th17, and Tregs. PPARγ has also been associated with B cells. The present review addresses these issues by placing PPARγ agonists in the context of adaptive immune responses and the relation of the activation of these receptors with the expression of cytokines involved in adaptive immunity.

The nuclear receptor PPARs as important regulators of T-cell functions and autoimmune diseases.

Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARΓ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4(+) T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.

Reciprocal Regulation of The Survival and Apoptosis of Th17 and Th1 Cells in The Colon

The immediate early response gene X-1 (IEX-1) is a stress-inducible gene involved in the regulation of cell growth, apoptosis and inflammation. Acute colitis was induced by treatment of IEX-1 knockout (KO) and wild type (WT) control mice with dextran sulfate sodium (DSS), whereas chronic colitis was induced in Rag-/- mice by adoptive transfer of CD4(+) CD45RB(hi) T cells isolated from the two strains of mice. The diseases and responses of lamina propria lymphocytes were analyzed in the mice. IEX-1 KO mice produced IL-17 in the colon significantly greater than WT control mice following DSS treatment owing to better survival and differentiation of both IL-17-secreting γδ T cells and Th17 cells. The altered level of IL-17 production contributed critically to the reduced colon inflammation in IEX-1 KO mice, and administration of neutralizing anti-IL-17 antibody increased susceptibility of the animal to the disease. Strikingly, in contrast to the better survival of T cells producing IL-17, lack of IEX-1 enhanced apoptosis in proinflammatory T cells producing interferon gamma (IFN-γ). Enhanced apoptosis in Th1 cells and better survival of Th17 cells may both result in a delayed onset of colitis in Rag-/- mice receiving pathogenic CD4(+) CD45RB(hi) T cells isolated from IEX-1 KO animals compared to those mice transferred with WT counterparts The present study demonstrates the refractoriness of IEX-1 knockout (KO) mice to DSS-induced colitis and diminished pathogenesis of IEX-1-deficient CD4(+) CD45RB(hi) T cells. These data demonstrate that IEX-1 reciprocally regulates T-cell survival and apoptosis in a subset-dependent fashion. Inhibition of IEX-1 may thus offer novel strategies for colitis treatment by simultaneous induction of apoptosis in proinflammatory Th1 cells while promoting the survival and differentiation of a protective T-cell subset.

CD5 through CK2 activation regulates B-1a B-cell survival, proliferation, and T-independent type 2 antibody response. (104.15)

Abstract CD5 expression is the characteristic feature of B-1a B-cells and B10 regulatory B-cells; however, the physiological role of this receptor on the development, persistence, and/or function of these B-cell populations remains undefined. To begin addressing this question we generated a CD5 mutant knock-in mouse (CD5ΔCK2BD) in which the serine threonine kinase, CK2, binding domain in the CD5-cytoplasmic tail was deleted. CD5 plays a critical role in regulating T-cell survival following antigen receptor engagement and this activity is dependent on CK2 activation. In the CD5ΔCK2BD mouse, the ability to activate CK2 is abrogated. B-1a B-cells in the CD5ΔCK2BD mouse turnover at a rate two-fold greater than that in WT mice. This increased turnover rate compensated for the decreased B-cell survival to maintain a near normal B-1a B-cell number in the peritoneal cavity. However, total serum natural IgM and IgA was significantly lower than that in WT mice. CD5ΔCK2BD B-1a B-cells proliferated poorly in response to anti-IgM stimulation but not LPS stimulation. The CD5ΔCK2BD mouse also exhibited an impaired anti-phosphatidylcholine (PC) response following immunization with heat killed S. pneumoniae, a prototypic B-1a B-cell response. Immune responses to T-independent type 1 antigen were not altered in the CD5ΔCK2BD mouse. These data provide the first evidence that CD5 has a direct role in regulating B-1a B-cell physiology.

Regulation of T cell-dendritic cell interactions by IL-7 governs T-cell activation and homeostasis

AbstractInterleukin-7 (IL-7) plays a central role in the homeostasis of the T-cell compartment by regulating T-cell survival and proliferation. Whether IL-7 can influence T-cell receptor (TCR) signaling in T cells remains controversial. Here, using IL-7–deficient hosts and TCR-transgenic T cells that conditionally express IL-7R, we examined antigen-specific T-cell responses in vitro and in vivo to viral infection and lymphopenia to determine whether IL-7 signaling influences TCR-triggered cell division events. In vitro, we could find no evidence that IL-7 signaling could costimulate T-cell activation over a broad range of conditions, suggesting that IL-7 does not directly tune TCR signaling. In vivo, however, we found an acute requirement for IL-7 signaling for efficiently triggering T-cell responses to influenza A virus challenge. Furthermore, we found that IL-7 was required for the enhanced homeostatic TCR signaling that drives lymphopenia-induced proliferation by a mechanism involving efficient contacts of T cells with dendritic cells. Consistent with this, saturating antigen-presenting capacity in vivo overcame the triggering defect in response to cognate peptide. Thus, we demonstrate a novel role for IL-7 in regulating T cell–dendritic cell interactions that is essential for both T-cell homeostasis and activation in vivo.

Galectin‐1 functions as a Th2 cytokine that selectively induces Th1 apoptosis and promotes Th2 function

Galectin-1 has been implicated in regulating T-cell survival, function, and Th1/Th2 balance in several mouse models, though the molecular and cellular basis of its immuno-modulatory activity has not been completely elucidated. Therefore, we examined galectin-1 expression and activity within differentiated murine Th1 and Th2 subsets. While recombinant galectin-1 specifically bound to both T-cell subsets, Th1 and Th2 T cells expressed distinct combinations of galectin-1-reactive epitopes and were differentially responsive to galectin-1 exposure. Indeed, Th1 cells were more susceptible to galectin-1-induced death than Th2 cells. Th2 protection from apoptosis was correlated with expression of anti-apoptotic galectin-3. Further, galectin-1 promoted TCR-induced type 2 cytokine production by Th2 cells. Differentiated Th2 cells constitutively expressed high levels of galectin-1 and can be induced to produce even higher levels of galectin-1 with restimulation, whereas comparable levels of galectin-1 in Th1 cells were only observed after restimulation. Co-culturing experiments using galectin-1(-/-) and galectin-1+/+ Th1 and Th2 T cells demonstrated that Th2-derived galectin-1 induced Th1 apoptosis, whereas Th1-derived galectin-1 promoted Th2 cytokine production. These studies identify galectin-1 as a cross-regulatory cytokine that selectively antagonizes Th1 survival, while promoting TCR-induced Th2 cytokine production.