The antigen-independent, strong proliferative responses of naive CD8+ T cells have been well demonstrated in a particular strain of mice lacking IL-2 receptors. This type of proliferation is mainly driven by common gamma-chain (γc) cytokines, such as IL-2, IL-7, and IL-15, present at abnormally high levels in these mice. Similarly, in the present study, we showed that mice lacking Janus kinase 3 (Jak3), a tyrosine kinase crucial for γc cytokine signaling, could induce strong proliferation of adoptively transferred naive CD8+ T cells. This proliferation was also independent of antigenic stimulation, but heavily dependent on IL-2, as evidenced by the failure of proliferation of adoptively transferred IL-2 receptor alpha- and beta-chain-deficient naive CD8+ T cells. Consistent with this, Jak3-/- mice showed elevated serum levels of IL-2 compared to wild-type mice, and interestingly, IL-2 production was due to high levels of accumulation of activated CD4+ T cells in Jak3-/- mice along with defective CD4+ T regulatory cells. Collectively, these findings reveal previously unidentified unique immune contexts of Jak3-/- mice that cause robust IL-2-driven T cell expansion and have a clinical implication for designing a treatment strategy for human patients with loss-of-function genetic mutations of Jak3.

Naïve CD8+ T cell quiescence is maintained at a steady state. Although this state of quiescence involves various cell-intrinsic and cell-extrinsic regulators, the mechanisms underlying this regulation remain incompletely understood. Here, we found that signal transducer and activator of transcription 1 (STAT1), a key transcription factor downstream of interferon receptor (IFNR) signaling, plays a cell-intrinsic role in maintaining naïve CD8+ T cell quiescence. STAT1-deficient mice showed enhanced proliferation of peripheral naïve CD8+ T cells, which resulted in an abnormal increase in the number of CD44hi memory/activated phenotype cells and an enlargement of secondary lymphoid tissues. This phenomenon was not observed in IFNR-deficient mice but was paradoxically dependent on type I interferon and its alternative signaling pathway via the STAT4–RagD–lysosomal mTORC1 axis. Collectively, these findings underline the importance of STAT1 in regulating the homeostasis of peripheral naïve CD8+ T cells by suppressing their responsiveness to homeostatic cues at a steady state.

The strength of the T cell receptor interaction with self-ligands affects antigen-specific immune responses. However, the precise function and underlying mechanisms are unclear. Here, we demonstrate that naive CD8+ T cells with relatively high self-reactivity are phenotypically heterogeneous owing to varied responses to type I interferon, resulting in three distinct subsets, CD5loLy6C-, CD5hiLy6C-, and CD5hiLy6C+ cells. CD5hiLy6C+ cells differ from CD5loLy6C- and CD5hiLy6C- cells in terms of gene expression profiles and functional properties. Moreover, CD5hiLy6C+ cells demonstrate more extensive antigen-specific expansion upon viral infection, with enhanced differentiation into terminal effector cells and reduced memory cell generation. Such features of CD5hiLy6C+ cells are imprinted in a steady-state and type I interferon dependence is observed even for monoclonal CD8+ T cell populations. These findings demonstrate that self-reactivity controls the functional diversity of naive CD8+ T cells by co-opting tonic type I interferon signaling.

Continuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naïve T cells but not memory cells. This surprising finding implies that T cell subsets may vary in their relative T-cell receptor (TCR) sensitivity. Here we show that in CD8⁺T cells TCR sensitivity correlates inversely with levels of CD5, a marker for strong self-MHC reactivity. We also show that TCR sensitivity is lower in memory CD8⁺ T cells than naïve cells. In both situations, TCR hypo-responsiveness applies only to short-term TCR signalling events and not to proliferation, and correlates directly with increased expression of a phosphatase, CD45 and reciprocal decreased expression of activated LCK. Inhibition by high CD45 on CD8⁺ T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens.

The gastrointestinal tract is the first organ directly affected by fasting. However, little is known about how fasting influences the intestinal immune system. Intestinal dendritic cells (DCs) capture antigens, migrate to secondary lymphoid organs, and provoke adaptive immune responses. We evaluated the changes of intestinal DCs in mice with short-term fasting and their effects on protective immunity against Listeria monocytogenes (LM). Fasting induced an increased number of CD103+CD11b- DCs in both small intestinal lamina propria (SILP) and mesenteric lymph nodes (mLN). The SILP CD103+CD11b- DCs showed proliferation and migration, coincident with increased levels of GM-CSF and C-C chemokine receptor type 7, respectively. At 24 h post-infection with LM, there was a significant reduction in the bacterial burden in the spleen, liver, and mLN of the short-term-fasted mice compared to those fed ad libitum. Also, short-term-fasted mice showed increased survival after LM infection compared with ad libitum-fed mice. It could be that significantly high TGF-β2 and Aldh1a2 expression in CD103+CD11b- DCs in mice infected with LM might affect to increase of Foxp3+ regulatory T cells. Changes of major subset of DCs from CD103+ to CD103- may induce the increase of IFN-γ-producing cells with forming Th1-biased environment. Therefore, the short-term fasting affects protection against LM infection by changing major subset of intestinal DCs from tolerogenic to Th1 immunogenic.