Autoimmune hepatitis (AIH) is known as a T cell–mediated disease. However, AIH patients refractory to conventional treatment have been successfully treated with anti‐CD20‐mediated B‐cell depletion. The aim of this project was to understand the immunological changes underlying the AIH remission caused by B‐cell depletion in an experimental model of AIH. C57BL/6 AIH mice, xenoimmunized with DNA coding for human liver antigens, were treated with a single dose of depleting mouse anti‐CD20 antibody at the peak of liver inflammation. Liver inflammation, alanine aminotransferase levels, chemokine (C‐X‐C) ligand 10 expression, and circulating B‐cell, autoantibody, and total immunoglobulin G levels were monitored following depletion. T‐cell and B‐cell phenotype and function were characterized. Administration of a single dose of anti‐CD20 resulted in a drastic reduction of liver inflammation accompanied by a significant reduction of alanine aminotransferase levels and of proinflammatory chemokine (C‐X‐C) ligand 10 expression. The treatment did not result in significant changes in total immunoglobulin G levels or autoantibodies. There were significantly more naive and less antigen‐experienced CD4+ and CD8+ T cells, and T‐cell proliferation was significantly reduced following anti‐CD20 treatment. B cells served as antigen‐presenting cells to CD4+ T cells. Anti‐CD20 treatment also led to a profound reduction of T follicular helper cells. Conclusion: B cells play an active role in the pathogenesis of AIH in antigen presentation processes and the modulation of T‐cell functions and influence the T follicular helper–cell population; this active role of B cells could explain the success of B‐cell depletion for remission of AIH despite its classification as a T cell–mediated autoimmune liver disease. (Hepatology 2015;62:1511–1523)

Some studies show eliminating senescent cells rejuvenate aged mice and attenuate deleterious effects of chemotherapy. Nevertheless, it remains unclear whether senescence affects immune cell function. We provide evidence that exposure of mice to ionizing radiation (IR) promotes the senescent‐associated secretory phenotype (SASP) and expression of p16INK4a in splenic cell populations. We observe splenic T cells exhibit a reduced proliferative response when cultured with allogenic cells in vitro and following viral infection in vivo. Using p16‐3MR mice that allow elimination of p16INK4a‐positive cells with exposure to ganciclovir, we show that impaired T‐cell proliferation is partially reversed, mechanistically dependent on p16INK4a expression and the SASP. Moreover, we found macrophages isolated from irradiated spleens to have a reduced phagocytosis activity in vitro, a defect also restored by the elimination of p16INK4a expression. Our results provide molecular insight on how senescence‐inducing IR promotes loss of immune cell fitness, which suggest senolytic drugs may improve immune cell function in aged and patients undergoing cancer treatment.

Exhaustion of CD8+ T cells severely impedes the adaptive immune response to chronic viral infections. Despite major advances in our understanding of the molecular regulation of exhaustion, the cytokines that directly control this process during chronicity remain unknown. We demonstrate a direct impact of IL-2 and IL-15, two common gamma-chain-dependent cytokines, on CD8+ T-cell exhaustion. Common to both cytokine receptors, the IL-2 receptor β (IL2Rβ) chain is selectively maintained on CD8 + T cells during chronic lymphocytic choriomeningitis virus and hepatitis C virus infections. Its expression correlates with exhaustion severity and identifies terminally exhausted CD8 + T cells both in mice and humans. Genetic ablation of the IL2Rβ chain on CD8 + T cells restrains inhibitory receptor induction, in particular 2B4 and Tim-3; precludes terminal differentiation of highly defective PD-1 hi effectors; and rescues memory T-cell development and responsiveness to IL-7-dependent signals. Together, we ascribe a previously unexpected role to IL-2 and IL-15 as instigators of CD8 + T-cell exhaustion during chronic viral infection.CD8 T cell | IL-2 | IL-15 | exhaustion | memory T cell

Eur. J. Immunol. 2015. 45: 3324-3338 Immunity to Infection 3325 tightly regulated process during which cells pass through an effector state before establishing long-term immune protection [1]. The recognition of pathogen-encoded peptides and their stimulation through costimulatory and cytokine signals initiate a specific transcriptional program critical for CD8 + T-cell lineage choices and functions [2,3]. As the memory T-cell pool is the direct progeny of these effectors cells, understanding the cellular and molecular mechanisms involved in the transition from cytotoxic T lymphocytes (CTLs) to memory cells constitutes an area of intense investigation.In the quest to dissect these mechanisms, two effector CD8 + T-cell populations were identified, based on their distinct expression of CD127 and KLRG1, and correlated with their propensity to persist and become memory [4][5][6]. While KLRG1 hi CD127 lo ShortLived Effector Cells (SLECs) are destined to become terminal effectors, KLRG1 lo CD127 hi Memory Precursor Effector Cells (MPECs) are fated to develop into long-lived memory cells. Since, multiple factors were shown to modulate the lineage choices between these two effector subsets. Limited antigenic stimulation preferentially commits effector CD8 + T cells toward a MPEC phenotype while prolonged antigen encounter promotes terminal SLEC differentiation [7,8]. Similarly, inflammatory cytokines (in particular IL-12) enhance SLEC generation in a T-bet-dependent manner, whereas low levels of inflammation favor memory formation [6,9]. Finally, cytokines that signal through the common gamma (γ c ) chain (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21) modify the CD8 + T-cell differentiation program upon infection and are indispensable for the generation of CD8 + memory T cells [10]. While IL-7promotes MPEC and CD8 + memory T-cell survival [11], IL-2 and IL-15 cooperate to sustain SLEC proliferation, differentiation, and survival [9,10,[12][13][14][15]. IL-15 is also a pivotal cytokine involved in the maintenance and homeostatic proliferation of the CD8 + memory T-cell pool [16,17]. Interestingly, IL-21, which is critical during chronic viral infection to limit exhaustion, has a minimal role on SLEC/MPEC lineage choices and CD8 + memory T-cell formation during an acute viral infection in help-independent infection models [18]. While the role of γ c -dependent signals on CD8 + memory T-cell development is indisputable, the biological impact of IL-2 and IL-15 on CD8 + memory T-cell functions remains controversial.Studies have demonstrated a critical role for IL-2 in the regulation of Blimp-1 and Eomes transcription [9,12], two transcription factors that have an opposite effect on the development of CD8 + memory T cells [19][20][21]. Moreover, some authors suggest that IL-2 present at the time of priming sustain the expansion of secondary effectors, while others do not [9,14,22,23]. Conversely, IL-15, a γ c -cytokine closely related to IL-2, appears dispensable for secondary effector expansion, while it may affect secondary e...

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