Denis Comte

Polyfunctional HCV-specific T-cell responses are associated with effective control of HCV replication

HCV infection has a severe course of disease in HIV/HCV co‐infection and in liver transplant recipients. However, the mechanisms involved remain unclear. Here, we evaluated functional profiles of HCV‐specific T‐cell responses in 86 HCV mono‐infected patients, 48 HIV/HCV co‐infected patients and 42 liver transplant recipients. IFN‐γ and IL‐2 production and ability of CD4 and CD8 T cells to proliferate were assessed after stimulation with HCV‐derived peptides. We observed that HCV‐specific T‐cell responses were polyfunctional in HCV mono‐infected patients, with presence of proliferating single IL‐2‐, dual IL‐2/IFN‐γ and single IFN‐γ‐producing CD4+ and dual IL‐2/IFN‐γ and single IFN‐γ‐producing CD8+ cells. In contrast, HCV‐specific T‐cell responses had an effector profile in HIV/HCV co‐infected individuals and liver transplant recipients with absence of single IL‐2‐producing HCV‐specific CD4+ and dual IL‐2/IFN‐γ‐producing CD8+ T cells. In addition, HCV‐specific proliferation of CD4+ and CD8+ T cells was severely impaired in HIV/HCV co‐infected patients and liver transplant recipients. Importantly, “only effector” T‐cell responses were associated with significantly higher HCV viral load and more severe liver fibrosis scores. Therefore, the present results suggest that immune‐based mechanisms may contribute to explain the accelerated course of HCV infection in conditions of HIV‐1 co‐infection and liver transplantation.

Differences in HCV‐specific T cell responses between chronic HCV infection and HIV/HCV co‐infection

Hepatitis C virus (HCV)‐specific CD4+ and CD8+ T cell responses were investigated using a panel of 728 overlapping peptides spanning the whole HCV genome in 47 HCV mono‐infected and 26 HIV/HCV co‐infected individuals using the IFN‐γ ELISPOT assay and flow cytometry. The frequency of HCV‐specific T cell responses was similar (∼40%) in both groups, but the breadth of the T cell responses tended to be reduced in HIV/HCV co‐infected individuals. Of interest, 23 new HCV‐derived epitopes were identified, and CD4+ HCV‐specific T cell responses were detected overall in a proportion similar to CD8+ T cell responses. A tendency towards a dominant CD8+ T cell response was associated with HIV/HCV co‐infection. HCV‐specific CD8+ T cells secreted both IL‐2 and IFN‐γ, although a reduction in the percentage of IL‐2/IFN‐γ‐secreting cells was observed in HIV/HCV co‐infected individuals. The increase in CD4+ T cell counts after antiretroviral therapy in HIV/HCV co‐infected individuals was not associated with restoration of HCV‐specific T cell responses. Altogether, these results provide new insights into the characterization of HCV‐specific T cell responses in HCV mono‐infected and HIV/HCV co‐infected individuals.

Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders.

Common variable immunodeficiency (CVID) is characterized by abnormally low levels of antibodies in the blood and dysfunctional immune cells called CD4+ T cells. Perreau et al. now show evidence that bacteria-fighting CD4+ T cells in these patients are in a state of exhaustion due to a constant leakage of normal gut bacteria into the bloodstream, possibly due to insufficient antibody levels.

T cells as a therapeutic target in SLE

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by a loss of tolerance to multiple endogenous antigens. SLE etiology remains largely unknown, despite recent insight into the immunopathogenesis of the disease. T cells are important in the development of the disease by amplifying the immune response and contributing to organ damage. Aberrant signaling, cytokine secretion, and tissue homing displayed by SLE T cells have been extensively studied and the underlying pathogenic molecular mechanisms are starting to be elucidated. T-cell-targeted treatments are being explored in SLE patients. This review is an update on the T-cell abnormalities and related therapeutic options in SLE.

CD160-Associated CD8 T-Cell Functional Impairment Is Independent of PD-1 Expression

Expression of co-inhibitory molecules is generally associated with T-cell dysfunction in chronic viral infections such as HIV or HCV. However, their relative contribution in the T-cell impairment remains unclear. In the present study, we have evaluated the impact of the expression of co-inhibitory molecules such as 2B4, PD-1 and CD160 on the functions of CD8 T-cells specific to influenza, EBV and CMV. We show that CD8 T-cell populations expressing CD160, but not PD-1, had reduced proliferation capacity and perforin expression, thus indicating that the functional impairment in CD160+ CD8 T cells may be independent of PD-1 expression. The blockade of CD160/CD160-ligand interaction restored CD8 T-cell proliferation capacity, and the extent of restoration directly correlated with the ex vivo proportion of CD160+ CD8 T cells suggesting that CD160 negatively regulates TCR-mediated signaling. Furthermore, CD160 expression was not up-regulated upon T-cell activation or proliferation as compared to PD-1. Taken together, these results provide evidence that CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression.

Selective Loss of Signaling Lymphocytic Activation Molecule Family Member 4–Positive CD8+ T Cells Contributes to the Decreased Cytotoxic Cell Activity in Systemic Lupus Erythematosus

Engagement of signaling lymphocytic activation molecule family member 4 (SLAMF4; CD244, 2B4) by its ligand SLAMF2 (CD48) modulates the function and expansion of both natural killer cells and a subset of cytotoxic CD8+ T cells. Because the cytotoxicity of CD8+ T lymphocytes isolated from patients with systemic lupus erythematosus (SLE) is known to be impaired, the aim of this study was to assess whether the expression and function of the checkpoint regulator SLAMF4 are altered on CD8+ T cells from patients with SLE.

Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus

Significance Systemic lupus erythematosus (SLE) is characterized by compromised IL-2 production and regulatory T-cell function. Studies in human SLE and in murine lupus models report that IL-2 replenishment ameliorates clinical lupus manifestations. Here we show that engagement of signaling lymphocytic activation molecule family 3 (SLAMF3), a coregulatory receptor of T cells, restores the sensitivity of SLE CD4+ T cells to IL-2, increasing their response to exogenous IL-2 via up-regulation of the IL-2Rα subunit. Moreover, activation of naïve CD4+ T cells with a monoclonal antibody directed against SLAMF3 promotes T helper cell differentiation toward a suppressive phenotype. These data suggest that the SLAMF3 receptor may be a promising therapeutic target in SLE. Signaling lymphocytic activation molecule family 3 (SLAMF3/Ly9) is a coregulatory molecule implicated in T-cell activation and differentiation. Systemic lupus erythematosus (SLE) is characterized by aberrant T-cell activation and compromised IL-2 production, leading to abnormal regulatory T-cell (Treg) development/function. Here we show that SLAMF3 functions as a costimulator on CD4+ T cells and influences IL-2 response and T helper cell differentiation. SLAMF3 ligation promotes T-cell responses to IL-2 via up-regulation of CD25 in a small mothers against decapentaplegic homolog 3 (Smad3)-dependent mechanism. This augments the activation of the IL-2/IL-2R/STAT5 pathway and enhances cell proliferation in response to exogenous IL-2. SLAMF3 costimulation promotes Treg differentiation from naïve CD4+ T cells. Ligation of SLAMF3 receptors on SLE CD4+ T cells restores IL-2 responses to levels comparable to those seen in healthy controls and promotes functional Treg generation. Taken together, our results suggest that SLAMF3 acts as potential therapeutic target in SLE patients by augmenting sensitivity to IL-2.

The selective loss of SLAMF4+ CD8+ T cells contributes to the decreased cytotoxic cell activity in systemic lupus erythematosus

Engagement of signaling lymphocytic activation molecule family member 4 (SLAMF4; CD244, 2B4) by its ligand SLAMF2 (CD48) modulates the function and expansion of both natural killer cells and a subset of cytotoxic CD8+ T cells. Because the cytotoxicity of CD8+ T lymphocytes isolated from patients with systemic lupus erythematosus (SLE) is known to be impaired, the aim of this study was to assess whether the expression and function of the checkpoint regulator SLAMF4 are altered on CD8+ T cells from patients with SLE.

Brief Report: CD4+ T Cells From Patients With Systemic Lupus Erythematosus Respond Poorly to Exogenous Interleukin-2

Imbalanced cytokine production by T cells characterizes both patients with systemic lupus erythematosus (SLE) and lupus‐prone mice and contributes to immune dysregulation. This study was undertaken to further investigate in detail the production of interleukin‐2 (IL‐2), interferon‐γ (IFNγ), IL‐4, and IL‐17A by CD4+ cell subsets in healthy subjects and patients with SLE, and the signaling response of CD4+ T cells in response to exogenous IL‐2.

ICER is requisite for Th17 differentiation

Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through the IL-6–STAT3 pathway and binds to the Il17a promoter, where it facilitates the accumulation of the canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4+ T cells to Th17 cells is impaired but can be rescued by forced overexpression of ICER. Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Similarly, both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. Importantly, we find ICER overexpressed in CD4+ T cells from patients with systemic lupus erythematosus. Collectively, our findings identify a unique role for ICER, which affects both organ-specific and systemic autoimmunity in a Th17-dependent manner.