The cIAP ubiquitin ligases sustain type 3 γδ T cells and ILC during aging to promote barrier immunity.

Early-life cues shape the immune system during adulthood. However, early-life signaling pathways and their temporal functions are not well understood. Herein, we demonstrate that the cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2), which are E3 ubiquitin ligases, sustain interleukin (IL)-17-producing γ δ T cells (γδT17) and group 3 innate lymphoid cells (ILC3) during late neonatal and prepubescent life. We show that cell-intrinsic deficiency of cIAP1/2 at 3-4 wk of life leads to downregulation of the transcription factors cMAF and RORγt and failure to enter the cell cycle, followed by progressive loss of γδT17 cells and ILC3 during aging. Mice deficient in cIAP1/2 have severely reduced γδT17 cells and ILC3, present with suboptimal γδT17 responses in the skin, lack intestinal isolated lymphoid follicles, and cannot control intestinal bacterial infection. Mechanistically, these effects appear to be dependent on overt activation of the non-canonical NF-κB pathway. Our data identify cIAP1/2 as early-life molecular switches that establish effective type 3 immunity during aging.

The neonatal microenvironment programs innate γδ T cells through the transcription factor STAT5.

IL-17-producing RORγt+ γδ T cells (γδT17 cells) are innate lymphocytes that participate in type 3 immune responses during infection and inflammation. Herein, we show that γδT17 cells rapidly proliferate within neonatal lymph nodes and gut, where, upon entry, they upregulate T-bet and coexpress IL-17, IL-22, and IFN-γ in a STAT3- and retinoic acid-dependent manner. Neonatal expansion was halted in mice conditionally deficient in STAT5, and its loss resulted in γδT17 cell depletion from all adult organs. Hyperactive STAT5 mutant mice showed that the STAT5A homolog had a dominant role over STAT5B in promoting γδT17 cell expansion and downregulating gut-associated T-bet. In contrast, STAT5B preferentially expanded IFN-γ-producing γδ populations, implying a previously unknown differential role of STAT5 gene products in lymphocyte lineage regulation. Importantly, mice lacking γδT17 cells as a result of STAT5 deficiency displayed a profound resistance to experimental autoimmune encephalomyelitis. Our data identify that the neonatal microenvironment in combination with STAT5 is critical for post-thymic γδT17 development and tissue-specific imprinting, which is essential for infection and autoimmunity.

The immune checkpoint receptor associated phosphatases SHP-1 and SHP-2 are not required for γδT17 cell development, activation, or skin inflammation.

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.

STAT3 but not STAT4 is critical for γδT17 cell responses and skin inflammation.

The transcription factors STAT3 and STAT4 are essential for lymphocyte differentiation and function. Interleukin (IL)-17 producing γδ T (γδT17) 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 γδT17 cells. We show that STAT3 sustains γδT17 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 γδT17 cells. Concomitantly, mice lacking STAT3 expression in γδT17 cells develop significantly reduced psoriasis-like inflammation. STAT3-deficient γδT17 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, γδT17 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 γδT17 cells and provide evidence for the requirement of STAT4 for optimal cytokine responses during inflammation.