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T cell development in the thymus is controlled by a multistep process. The NF-κB pathway regulates T cell development as well as T cell activation at multiple differentiation stages. The linear ubiquitin chain assembly complex (LUBAC) is composed of Sharpin, HOIL-1L and HOIP, and it is crucial for regulating the NF-κB and cell death pathways. However, little is known about the roles of LUBAC in T-cell development and activation. Here, we show that in T-HOIP Δlinear mice lacking the ubiquitin ligase activity of LUBAC, thymic CD4 + or CD8 + T cell numbers were markedly reduced with severe defects in NKT cell development. HOIP Δlinear CD4 + T cells failed to phosphorylate IκBα and JNK through T cell receptor-mediated stimulation. Mature CD4 + and CD8 + T cells in T-HOIP Δlinear mice underwent apoptosis more rapidly than control T cells, and it was accompanied by lower CD127 expression on CD4 + CD24 low and CD8 + CD24 low T cells in the thymus. The enforced expression of CD127 in T-HOIP Δlinear thymocytes rescued the development of mature CD8 + T cells. Collectively, our results showed that LUBAC ligase activity is key for the survival of mature T cells, and suggest multiple roles of the NF-κB and cell death pathways in activating or maintaining T cell-mediated adaptive immune responses.

Upon their recognition of antigens presented by the MHC, T cell proliferation is vital for clonal expansion and the acquisition of effector functions, which are essential for mounting adaptive immune responses. The CD98 heavy chain (CD98hc, Slc3a2) plays a crucial role in the proliferation of both CD4+ and CD8+ T cells, although it is unclear if CD98hc directly regulates the T cell effector functions that are not linked with T cell proliferation in vivo. Here, we demonstrate that CD98hc is required for both CD4+ T cell proliferation and Th1 functional differentiation. T cell-specific deletion of CD98hc did not affect T cell development in the thymus. CD98hc-deficient CD4+ T cells proliferated in vivo more slowly as compared with control T cells. C57BL/6 mice lacking CD98hc in their CD4+ T cells could not control Leishmania major infections due to lowered IFN-γ production, even with massive CD4+ T cell proliferation. CD98hc-deficient CD4+ T cells exhibited lower IFN-γ production compared with wild-type T cells, even when comparing IFN-γ expression in cells that underwent the same number of cell divisions. Therefore, these data indicate that CD98hc is required for CD4+ T cell expansion and functional Th1 differentiation in vivo, and suggest that CD98hc might be a good target for treating Th1-mediated immune disorders.

CD4(+) T cell activation is controlled by signaling through the T cell receptor in addition to various co-receptors, and is also affected by their interactions with effector and regulatory T cells in the microenvironment. Inflammatory bowel diseases (IBD) are caused by the persistent activation and expansion of auto-aggressive CD4(+) T cells that attack intestinal epithelial cells. However, the molecular basis for the persistent activation of CD4(+) T cells in IBD remains unclear. In this study, we investigated how the CD98 heavy chain (CD98hc, Slc3a2) affected the development of colitis in an experimental animal model. Transferring CD98hc-deficient CD4(+)CD25(-) T cells into Rag2(-/-) mice did not cause colitis accompanied by increasing Foxp3(+) inducible regulatory T cells. By comparison, CD98hc-deficient naturally occurring regulatory T cells (nTregs) had a decreased capability to suppress colitis induced by CD4(+)CD25(-) T cells, although CD98hc-deficient mice did not have a defect in the development of nTregs. Blocking CD98hc with an anti-CD98 blocking antibody prevented the development of colitis. Our results indicate that CD98hc regulates the expansion of autoimmune CD4(+) T cells in addition to controlling nTregs functions, which suggests the CD98hc as an important target molecule for establishing strategies for treating colitis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

CD4(+) helper T (Th) cells differentiate toward distinct effector cell lineages characterized by their distinct cytokine expression patterns and functions. Multiple Th cell populations secrete IL-22 that contributes to both protective and pathological inflammatory responses. Although the differentiation of IL-22-producing Th cells is controlled by the aryl hydrocarbon receptor (AhR), little is known about the regulatory mechanisms inducing physiological stimulators for AhR. Here, we show that Notch signaling enhances IL-22 production by CD4(+) T cells by a mechanism involving AhR stimulation. Notch-mediated stimulation of CD4(+) T cells increased the production of IL-22 even in the absence of STAT3. CD4(+) T cells from RBP-J-deficient mice had little ability to produce IL-22 through T cell receptor-mediated stimulation. RBP-J-deficient mice were highly susceptible to the detrimental immunopathology associated with ConA-induced hepatitis with little IL-22 production by CD4(+) T cells. Exogenous IL-22 protected RBP-J-deficient mice from ConA-induced hepatitis. Notch signaling promoted production of endogenous stimulators for AhR, which further augmented IL-22 secretion. Our studies identify a Notch-AhR axis that regulates IL-22 expression and fine-tunes immune system control of inflammatory responses.

T cells express diverse antigen-specific receptors and are required for eradicating pathogens and transformed cells. T cells expressing CD4 acquire helper effector functions and those expressing CD8 exert cytotoxic activity after antigen recognition. The protein-tyrosine phosphatase, receptor type kappa (PTPRKappa) is mutated in LEC rats, resulting in impaired CD4(+) T cell development in the thymus. However, the molecular mechanism of PTPRK controlling CD4(+) T cell development remains unclear. We demonstrate herein that inhibition of PTPRK by transducing a dominant negative form of the intracellular domain of PTPRK (PTPRK-ICD-DN) in bone marrow-derived stem cells suppresses the development of CD4(+) T cells. The inhibition of PTPRK by PTPRK-ICD-DN or short-hairpin RNA for PTPRK attenuates ERK1/2 phosphorylation in T cells after PMA and ionomycin stimulation. Total thymocytes from LEC rats also showed weaker phosphorylation of ERK1/2 after PMA and ionomycin stimulation than control thymocytes. Furthermore, inhibition of PTPRK by PTPRK-ICD-DN suppressed MEK1/2 and c-Raf phosphorylation, which is required for ERK1/2 phosphorylation. These data indicate that PPTRK positively regulates ERK1/2 phosphorylation, which impacts CD4(+) T cell development.