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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.

STAT1 serves as a gatekeeper for naïve CD8 + T cell homeostasis by restraining type I IFN-STAT4-mTOR signaling axis.

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.

Capicua (CIC) is a transcriptional repressor that regulates several developmental processes. CIC deficiency results in lymphoproliferative autoimmunity accompanied by expansion of CD44hiCD62Llo effector/memory and follicular Th cell populations. Deletion of Cic alleles in hematopoietic stem cells (Vav1-Cre-mediated knockout of Cic) causes more severe autoimmunity than that caused by the knockout of Cic in CD4+CD8+ double positive thymocytes (Cd4-Cre-mediated knockout of Cic). In this study, we compared splenic CD4+ T cell activation and proliferation between whole immune cell-specific Cic-null (Cicf/f;Vav1-Cre) and T cell-specific Cic-null (Cicf/f;Cd4-Cre) mice. Hyperactivation and hyperproliferation of CD4+ T cells were more apparent in Cicf/f;Vav1-Cre mice than in Cicf/f;Cd4-Cre mice. Cicf/f;Vav1-Cre CD4+ T cells more rapidly proliferated and secreted larger amounts of IL-2 upon TCR stimulation than did Cicf/f;Cd4-Cre CD4+ T cells, while the TCR stimulation-induced activation of the TCR signaling cascade and calcium flux were comparable between them. Mixed wild-type and Cicf/f;Vav1-Cre bone marrow chimeras also exhibited more apparent hyperactivation and hyperproliferation of Cic-deficient CD4+ T cells than did mixed wild-type and Cicf/f;Cd4-Cre bone marrow chimeras. Taken together, our data demonstrate that CIC deficiency at the beginning of T cell development endows peripheral CD4+ T cells with enhanced T cell activation and proliferative capability.

Continuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naive 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 naive 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. Naive T cells establish self-tolerance via negative selection of cells with strong reactivity for self-peptide/MHC complexes, but undergo T-cell receptor (TCR) desensitisation when leaving the thymus. Here, Choet al.show that TCR desensitisation correlates with cell-surface density of the phosphatase CD45.

Background & Aims Obesity and metabolic syndrome have been associated with alterations to the intestinal microbiota. However, few studies examined the effects of obesity on the intestinal immune system. We investigated changes in subsets of intestinal CD4 + T-helper (T H ) cells with obesity and the effects of gut-tropic T H 17 cells in mice on a high-fat diet (HFD). Methods We isolated immune cells from small intestine and adipose tissue of C57BL/6 mice fed a normal chow diet or a HFD for 10 weeks and analyzed the cells by flow cytometry. Mice fed a vitamin A−deficient HFD were compared with mice fed a vitamin A−sufficient HFD. Obese RAG1-deficient mice were given injections of only regulatory T cells or a combination of regulatory T cells and T H 17 cells (wild type or deficient in integrin β7 subunit or interleukin 17 [IL17]). Mice were examined for weight gain, fat mass, fatty liver, glucose tolerance, and insulin resistance. Fecal samples were collected before and after T cell transfer and analyzed for microbiota composition by metagenomic DNA sequencing and quantitative polymerase chain reaction. Results Mice placed on a HFD became obese, which affected the distribution of small intestinal CD4 + T H cells. Intestinal tissues from obese mice had significant reductions in the proportion of T H 17 cells but increased proportion of T H 1 cells, compared with intestinal tissues from nonobese mice. Depletion of vitamin A in obese mice further reduced the proportion of T H 17 cells in small intestine; this reduction correlated with more weight gain and worsening of glucose intolerance and insulin resistance. Adoptive transfer of in vitro−differentiated gut-tropic T H 17 cells to obese mice reduced these metabolic defects, which required the integrin β7 subunit and IL17. Delivery of T H 17 cells to intestines of mice led to expansion of commensal microbes associated with leanness. Conclusions In mice, intestinal T H 17 cells contribute to development of a microbiota that maintains metabolic homeostasis, via IL17. Gut-homing T H 17 cells might be used to reduce metabolic disorders in obese individuals.

A gastric carcinoma with the endoscopic features resembling a submucosal tumor (SMT) is rare, and reportedly accounting for 0.1% to 0.63% of all resected gastric carcinomas in Japan. A diagnosis of a SMT-like gastric carcinoma is often difficult as the tumors are almost entirely covered with normal mucosa. Furthermore mucinous gastric adenocarcinoma is uncommon histologic subtype of gastric cancer. These tumors are detected mostly in an advanced stage and rarely in an early stage. Early mucinous gastric adenocarcinoma is characterized as an elevated lesion resembling SMT due to abundant mucin pools in the submucosa. Here we report one case of SMT-like mucinous gastric adenocarcinoma, diagnosed by the usual endoscopic biopsy and treated with surgery.