No abstract

The transcription factors STAT3 and STAT4 are essential for lymphocyte differentiation and function. Interleukin (IL)-17 producing cd T (cdT17) cells are innate lymphocytes important for anti-bacterial and inflammatory responses at barrier surfaces. Herein, we examine the role of STAT3 and STAT4 in regulating the homeostasis, activation, and pathogenicity of cdT17 cells. We show that STAT3 sustains cdT17 numbers in the skin but not in the lymph nodes, while STAT4 deficiency does not affect their homeostasis. Similarly, STAT3 but not STAT4 is essential for IL-23-induced IL-22 production by cdT17 cells. Concomitantly, mice lacking STAT3 expression in cdT17 cells develop significantly reduced psoriasislike inflammation. STAT3-deficient cdT17 cells fail to expand and to upregulate IL-17A, IL-17F, and IL-22 in response to psoriatic stimuli. Although STAT4-deficient animals develop psoriasis-like disease, cdT17 cells in these mice are defective in IL-17F production. Collectively, our data demonstrate for the first time a critical role for STAT3 in orchestrating the homeostasis and pathogenicity of cdT17 cells and provide evidence for the requirement of STAT4 for optimal cytokine responses during inflammation.

T cells of the gamma delta (γδ) lineage are evolutionary conserved from jawless to cartilaginous and bony fish to mammals and represent the "swiss army knife" of the immune system capable of antigen-dependent or independent responses, memory, antigen presentation, regulation of other lymphocytes, tissue homeostasis, and mucosal barrier maintenance, to list a few. Over the last 10 years, γδ T cells that produce the cytokine IL-17 (γδT17) have taken a leading position in our understanding of how our immune system battles infection, inflicts tissue damage during inflammation, and gets rewired by the tumor microenvironment. A lot of what we know about γδT17 cells stems from mouse models, however, increasing evidence implicates these cells in numerous human diseases. Herein, we aim to give an overview of the most common mouse models that have been used to study the role of γδT17 cells in infection, inflammation, and cancer, while at the same time we will evaluate evidence for their importance in humans. We hope and believe that in the next 10 years, means to take advantage of the protective and destructive properties of γδ T and in particular γδT17 cells will be part of our standard immunotherapy toolkit.

Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-κB signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4+ T cells with SMs during T helper 17 (TH17) cell differentiation disrupted the balance between two antagonistic transcription factor modules. Moreover, proteomics analysis revealed that SMs altered the abundance of proteins associated with cell cycle, mitochondrial activity, and the balance between canonical and noncanonical NF-κB signaling. Whereas SMs inhibited interleukin-17 (IL-17) production and ameliorated TH17 cell–driven inflammation, they stimulated IL-22 secretion. Mechanistically, SM-mediated activation of NF-κB–inducing kinase (NIK) and the transcription factors RelB and p52 directly suppressed Il17a expression and IL-17A protein production, as well as the expression of a number of other immune genes. Induction of IL-22 production correlated with the NIK-dependent reduction in cMAF protein abundance and the enhanced activity of the aryl hydrocarbon receptor. Last, SMs also increased IL-9 and IL-13 production and, under competing conditions, favored the differentiation of naïve CD4+ T cells into TH2 cells rather than TH17 cells. These results demonstrate that SMs shape the gene expression and protein profiles of TH17 cells and inhibit TH17 cell–driven autoimmunity.

IL‐17‐producing gamma delta (γδT17) cells are innate lymphocytes critical for antibacterial protection at barrier surfaces such as the skin but also highly pathogenic during inflammation. It is therefore important to understand the cellular and molecular mechanisms that could counter‐balance overt γδT17 cell activation. Immune checkpoint receptors (ICRs) deliver inhibitory signals to activated lymphocytes and have been implicated as negative regulators of mouse γδT17 cells. In this report, we investigated the cytokine signals that induce ICR expression on γδT17 cells and studied the in vivo role of the Src‐homology‐2 phosphatases 1 and 2 (SHP‐1 and SHP‐2) in the context of γδT17‐induced psoriasis. We found that surface expression of ICRs can be induced by cytokines; however, SHP‐1 or SHP‐2 could not inhibit γδT17 responses. In this regard, conditional deletion of SHP‐1, SHP‐2, or both did no impact γδT17 cell development, expansion, cytokine production, or skin pathology.