Accumulating evidence suggests a role for γδ T cells as unexpected drivers of tumor development and progression. These protumoral γδ T cells are abundant in the tumor microenvironment in both mouse and human. They promote tumor progression by 1) inducing an immunosuppressive tumor microenvironment and angiogenesis via cytokine production; by 2) functioning as Treg/Th2-like cells; by 3) interfering with dendritic cell effector function; and by 4) inhibiting antitumor adaptive T cell immunity via the PD-1/PD-L1 pathway. Understanding how these cells are regulated and what their specific role in cancer is will provide insight for developing approaches that specifically target these cells and can thus improve the efficacy of cancer immunotherapies.
The biological activities of chemokine (C‐C motif) ligand 2 (CCL2) are mediated via C‐C chemokine receptor‐2 (CCR2). Increased CCL2 level is associated with metastasis of many cancers. In our study, we investigated the role of the CCL2/CCR2 axis in the development of spontaneous intestinal tumorigenesis using the ApcMin/+ mouse model. Ablation of CCR2 in ApcMin/+ mice significantly increased the overall survival and reduced intestinal tumor burden. Immune cell analysis showed that CCR2−/−ApcMin/+ mice exhibited significant reduction in the myeloid cell population and increased interferon γ (IFN‐γ) producing T cells both in spleen and mesenteric lymph nodes compared to ApcMin/+ mice. The CCR2−/−ApcMin/+ tumors showed significantly reduced levels of interleukin (IL)‐17 and IL‐23 and increased IFN‐γ and Granzyme B compared to ApcMin/+ tumors. Transfer of CCR2+/+ApcMin/+ CD4+ T cells into Rag2−/− mice led to development of colitis phenotype with increased CD4+ T cells hyper proliferation and IL‐17 production. In contrast, adoptive transfer of CCR2−/−ApcMin/+ CD4+ T cells into Rag2−/− mice failed to enhance colonic inflammation or IL‐17 production. These results a suggest novel additional role for CCR2, where it regulates migration of IL‐17 producing cells mediating tumor‐promoting inflammation in addition to its role in migration of tumor associated macrophages.
IL-17 producing γδ T cells (γδ-T17) are major players in promoting several autoimmune inflammatory diseases and cancers. However, γδ-T17 homeostatic regulation has not been fully understood. In naïve, adult IL-17r-/- and IL-17A-/-/F-/- mice we observed higher frequencies of total γδ T cells, predominantly γδ-T17, in the lung, spleen, gut, LN and skin but not in the thymus. We hypothesized that the IL-17-IL-17r axis regulates peripheral γδ-T17 homeostasis. Two different regulatory pathways were identified to be involved in this regulation: extrinsically through microbiota-host interaction and intrinsically through IL-17r-IL-7r signaling interaction. The extrinsic pathway was discovered in vitro using CFSE-labeled IL-17r-/- lymphocytes that had endogenous γδ-T17 proliferation dependent upon DCs, particular CD103+ DCs, and IL-1β. Using mice delivered from IL-17r-/- pregnant females treated either with lymphotoxin beta receptor-Ig to remove LNs or antibiotics (ampicillin, vancomycin, neomycin, and metronidazole) to deplete gut microbiota we found significantly decreased frequency of γδ-T17 in peripheral tissues. Also, intrinsically IL-17r-/- γδ-T17 expressed higher levels of RORγt that suppressed BTLA expression, which is a known inhibitor of IL-7-driven γδ-T17 proliferation. Taken together, our findings suggest that the IL-17-IL-17r axis regulates γδ-T17 via both intrinsic and extrinsic pathways.
Recently, others and we have identified a unique subset of γδ T cells in dermis that is capable of producing IL-17. Dermal γδ T cells have been demonstrated to play a critical role in the psoriasis pathogenesis. However, it is still unclear how these cells are developed and regulated. In this study, we found that dermal γδ T cells were mainly developed from the thymus. Surprisingly, there is also an extrathymic pathway for these cells development as our data showed that bone marrow cells alone could also reconstitute the dermal γδ T cells in the mice absence of thymus (Nude mice). Although most of dermal γδ T cells are skin bona-fide residents, there were a part of γδ T cells migrated from the periphery. Such trafficking process required chemokine receptor 6. In the periphery, we found that both IL-23 and IL-1β promoted dermal γδ T cells proliferation. However, IL-23-induced dermal γδ T cell proliferation was mainly dependent on IL-1β. Additionally, IL-1β synergized with IL-23 to produce large amounts of IL-17 by dermal γδ T cells. Moreover, mice with IL-1RI deficiency had significantly decreased epidermal thickness and neutrophil infiltration induced by IL-23 or Imiquimod. Taken together, we demonstrate the development, peripheral trafficking and regulation of dermal γδ T cells, which provides new insights into understanding the biology of this newly discovered cell population and implies new mechanisms involved in the pathogenesis of skin inflammation such as psoriasis.
Dermal γδ T cells are professional IL-17-producing γδ T cells and play a critical role in skin inflammation. However, their development and peripheral regulation are still largely unknown. In this study, we demonstrated that dermal γδ T cells developed from fetal thymus and underwent homeostatic proliferation after birth with diversified TCR repertoire, mainly including Vγ4 and Vγ6. Thymus is absolutely required for dermal γδ T cell development. IL-17-producing Vγ6 T cells were bona fide resident in dermis and were reconstituted from fetal thymus while IL-17-producing Vγ4 dermal γδ T cells were mainly from bone marrow, suggesting precursors of dermal Vγ4 T cells may require extrathymic environment for maturation and gaining skin-homing property. In addition, we found that Vγ6 T cells were pathogenic to induce skin inflammation. Mice reconstituted with Vγ6 developed psoriasis-like skin inflammation upon IMQ application whereas Vγ4 T cells were preferentially expanded and the major IL-17 producer in IMQ-treated naïve mice. Although IL-23 and IL-1β were capable of driving dermal Vγ4 and Vγ6 T cell proliferation, IL-17 production was mainly from Vγ4 and IL-1 signaling was essential. These studies reveal a differential developmental requirement and peripheral regulation for IL-17-producing dermal Vγ6 and Vγ4 T cells. This work is supported by a grant from the National Psoriasis Foundation.
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