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Endosomal nucleic acid sensing by Toll-like receptors (TLRs) is central to antimicrobial immunity and several autoimmune conditions such as systemic lupus erythematosus (SLE). The innate immune adaptor TASL mediates, via the interaction with SLC15A4, the activation of IRF5 downstream of human TLR7, TLR8 and TLR9, but the pathophysiological functions of this axis remain unexplored. Here we show that SLC15A4 deficiency results in a selective block of TLR7/9-induced IRF5 activation, while loss of TASL leads to a strong but incomplete impairment, which depends on the cell type and TLR engaged. This residual IRF5 activity is ascribed to a previously uncharacterized paralogue, Gm6377 , named here TASL2. Double knockout of TASL and TASL2 (TASL DKO ) phenocopies SLC15A4-deficient feeble mice showing comparable impairment of innate and humoral responses. Consequently, TASL DKO mice fail to control chronic LCMV infection, while being protected in a pristane-induced SLE disease model. Our study thus demonstrates the critical pathophysiological role of SLC15A4 and TASL/TASL2 for TLR7/9-driven inflammatory responses, further supporting the therapeutic potential of targeting this complex in SLE and related diseases. TASL is an adaptor molecule bridging Toll-like receptor signalling and transcription activation by IRF5. Here the authors show that TASL deficiency impacts TLR7/9 responses, and that a TASL paralogue, Gm6377/TASL2, also contributes to IRF5 activation, as dual TASL/TASL2 deficiency dampens both protective and pathogenic inflammatory responses in mice.

Regulatory T cells (Tregs) are indispensable for maintaining self-tolerance by suppressing conventional T cells. On the other hand, Tregs promote tumor growth by inhibiting anti-cancer immunity. In this study, we identified that Tregs increase the quorum of self-reactive CD8 + T cells required for the induction of experimental autoimmune diabetes in mice. Their major suppression mechanism is limiting available IL-2, an essential T-cell cytokine. Specifically, Tregs inhibit the formation of a previously uncharacterized subset of antigen-stimulated KLRK1 + IL7R + (KILR) CD8 + effector T cells, which are distinct from conventional effector CD8 + T cells. KILR CD8 + T cells show a superior cell killing abilities in vivo. The administration of agonistic IL-2 immunocomplexes phenocopies the absence of Tregs, i.e., it induces KILR CD8 + T cells, promotes autoimmunity, and enhances anti-tumor responses in mice. Counterparts of KILR CD8 + T cells were found in the human blood, revealing them as a potential target for immunotherapy.

The cytokine TNF can trigger highly proinflammatory RIPK1-dependent cell death. Here, we show that the two adapter proteins, TANK and AZI2, suppress TNF-induced cell death by regulating the activation of TBK1 kinase. Mice lacking either TANK or AZI2 do not show an overt phenotype. Conversely, animals deficient in both adapters are born in a sub-Mendelian ratio and suffer from severe multi-organ inflammation, excessive antibody production, male sterility, and early mortality, which can be rescued by TNFR1 deficiency and significantly improved by expressing a kinase-dead form of RIPK1. Mechanistically, TANK and AZI2 both recruit TBK1 to the TNF receptor signaling complex, but with distinct kinetics due to interaction with different complex components. While TANK binds directly to the adapter NEMO, AZI2 is recruited later via deubiquitinase A20. In summary, our data show that TANK and AZI2 cooperatively sustain TBK1 activity during different stages of TNF receptor assembly to protect against autoinflammation. Dysregulation of the TNF receptor signaling complex (TNF-RSC) promotes the onset of autoinflammatory conditions. Here the authors show that two adapter proteins, TANK and AZI2, mediate the recruitment of the kinase TBK1 to TNF-RSC to protect the mice from TNF-induced cell death and autoinflammation.

Mature T cells are selected for recognizing self-antigens with low to intermediate affinity in the thymus. Recently, the relative differences in self-reactivity among individual T-cell clones were appreciated as important factors regulating their fate and immune response, but the role of self-reactivity in T-cell biology is incompletely understood. We addressed the role of self-reactivity in T-cell diversity by generating an atlas of mouse peripheral CD8 + T cells, which revealed two unconventional populations of antigen-inexperienced T cells. In the next step, we examined the steady-state phenotype of monoclonal T cells with various levels of self-reactivity. Highly self-reactive clones preferentially differentiate into antigen-inexperienced memory-like cells, but do not form a population expressing type I interferon-induced genes, showing that these two subsets have unrelated origins. The functional comparison of naïve monoclonal CD8 + T cells specific to the identical model antigen did not show any correlation between the level of self-reactivity and the magnitude of the immune response.

Transmembrane adaptor proteins (TRAPs) are important organisers for the transduction of immunoreceptor-mediated signals. Prr7 is a TRAP that regulates T cell receptor (TCR) signalling and potently induces cell death when overexpressed in human Jurkat T cells. Whether endogenous Prr7 has a similar functional role is currently unknown. To address this issue, we analysed the development and function of the immune system in Prr7 knockout mice. We found that loss of Prr7 partially impairs development of single positive CD4+ T cells in the thymus but has no effect on the development of other T cell subpopulations, B cells, NK cells, or NKT cells. Moreover, Prr7 does not affect the TCR signalling pathway as T cells derived from Prr7 knockout and wild-type animals and stimulated in vitro express the same levels of the activation marker CD69, and retain their ability to proliferate and activate induced cell death programs. Importantly, Prr7 knockout mice retained the capacity to mount a protective immune response when challenged with Listeria monocytogenes infection in vivo. In addition, T cell effector functions (activation, migration, and reactivation) were normal following induction of experimental autoimmune encephalomyelitis (EAE) in Prr7 knockout mice. Collectively, our work shows that loss of Prr7 does not result in a major immune system phenotype and suggests that Prr7 has a dispensable function for TCR signalling.

Interleukin-17A (IL-17A) is a key mediator of protective immunity to yeast and bacterial infections but also drives the pathogenesis of several autoimmune diseases, such as psoriasis or psoriatic arthritis. Here we show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor (IL-17R). CMTM4 constitutively associated with IL-17R subunit C to mediate its stability, glycosylation and plasma membrane localization. Both mouse and human cell lines deficient in CMTM4 were largely unresponsive to IL-17A, due to their inability to assemble the IL-17R signaling complex. Accordingly, CMTM4-deficient mice had a severe defect in the recruitment of immune cells following IL-17A administration and were largely resistant to experimental psoriasis, but not to experimental autoimmune encephalomyelitis. Collectively, our data identified CMTM4 as an essential component of IL-17R and a potential therapeutic target for treating IL-17-mediated autoimmune diseases.Draber and colleagues show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor.

The kinase LCK and CD4/CD8 co-receptors are crucial components of the T cell antigen receptor (TCR) signaling machinery, leading to key T cell fate decisions. Despite decades of research, the roles of CD4–LCK and CD8–LCK interactions in TCR triggering in vivo remain unknown. In this study, we created animal models expressing endogenous levels of modified LCK to resolve whether and how co-receptor-bound LCK drives TCR signaling. We demonstrated that the role of LCK depends on the co-receptor to which it is bound. The CD8-bound LCK is largely dispensable for antiviral and antitumor activity of cytotoxic T cells in mice; however, it facilitates CD8 + T cell responses to suboptimal antigens in a kinase-dependent manner. By contrast, the CD4-bound LCK is required for efficient development and function of helper T cells via a kinase-independent stabilization of surface CD4. Overall, our findings reveal the role of co-receptor-bound LCK in T cell biology, show that CD4- and CD8-bound LCK drive T cell development and effector immune responses using qualitatively different mechanisms and identify the co-receptor–LCK interactions as promising targets for immunomodulation. Stepanek and colleagues demonstrate that the LCK kinase associated with CD4 or CD8 co-receptors has kinase-dependent and kinase-independent roles in T cell activation.

WW domain binding protein 1‐like (WBP1L), also known as outcome predictor of acute leukaemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which correlates with ETV6‐RUNX1 (t(12;21)(p13;q22)) translocation and favourable prognosis in childhood leukaemia. It has a broad expression pattern in haematopoietic and in non‐haematopoietic cells. However, its physiological function has been unknown. Here, we show that WBP1L negatively regulates signalling through a critical chemokine receptor CXCR4 in multiple leucocyte subsets and cell lines. We also show that WBP1L interacts with NEDD4‐family ubiquitin ligases and regulates CXCR4 ubiquitination and expression. Moreover, analysis of Wbp1l‐deficient mice revealed alterations in B cell development and enhanced efficiency of bone marrow cell transplantation. Collectively, our data show that WBP1L is a novel regulator of CXCR4 signalling and haematopoiesis.

Autoimmune Addison’s disease (AD) is a rare, life-threatening endocrine disorder caused by immune-mediated destruction of the adrenal cortex. AD frequently occurs in patients with autoimmune polyglandular syndrome type 1, a monogenic autoimmune syndrome caused by AIRE deficiency. The pathogenesis of AD remains poorly understood due to the lack of suitable animal models. Here, we established a mouse model of Experimental Autoimmune Adrenalitis by targeting the adrenal self-antigen CYP11A1. Immunization with CYP11A1-derived peptides elicited clonal expansion of CYP11A1-specific T-cell clones and the adrenal infiltration of CD4+ and CD8+ T cells and myeloid cells. Inflammation progressed to granulomatous lesions and culminated in adrenal insufficiency in AIRE-deficient mice with impaired central tolerance. A modification of the model based an adoptive transfer of polyclonal CYP11A1-stimulated CD4+ T cells into T-cell deficient hosts accelerated adrenal dysfunction. In contrast, IFNG-deficient CD4+ T cells induced only mild granulomatous inflammation and failed to cause overt adrenal insufficiency. These findings established a tractable mouse model for dissecting AD pathogenesis and identified CD4+ T cell-derived IFNG as a key effector of adrenal autoimmunity, providing a preclinical platform for testing targeted immunotherapies.