A major population of mucosal memory CD4+ T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality

Abstract

Mucosal tissues contain large numbers of memory CD4+ T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4+ T cells at barrier surfaces that coexpress interleukin-18 receptor alpha (IL-18Rα) and death receptor-3 (DR3), and display innate lymphocyte functionality. The cytokines IL-15 or the DR3 ligand tumor necrosis factor (TNF)-like cytokine 1A (TL1a) induced memory IL-18Rα+DR3+CD4+ T cells to produce interferon-γ, TNF-α, IL-6, IL-5, IL-13, granulocyte–macrophage colony-stimulating factor (GM-CSF), and IL-22 in the presence of IL-12/IL-18. TL1a synergized with IL-15 to enhance this response, while suppressing IL-15-induced IL-10 production. TL1a- and IL-15-mediated cytokine induction required the presence of IL-18, whereas induction of IL-5, IL-13, GM-CSF, and IL-22 was IL-12 independent. IL-18Rα+DR3+CD4+ T cells with similar functionality were present in human skin, nasal polyps, and, in particular, the intestine, where in chronic inflammation they localized with IL-18-producing cells in lymphoid aggregates. Collectively, these results suggest that human memory IL-18Rα+DR3+ CD4+ T cells may contribute to antigen-independent innate responses at barrier surfaces.

Oral epithelial cells orchestrate innate type 17 responses to Candida albicans through the virulence factor candidalysin

“…Similarly, in the eye, γδ-T cells specific for an ocular commensal bacterium can provide protection from C. albicans through IL-17 production (48). Innate functions in pulmonary memory Th2 cells have been described that manifest effector responses without engaging the TCR (49), and memory T cells with innate-like functions have been reported in human mucosae and skin (50). These findings collectively indicate that tissue-resident T cells can be co-opted to function in an innate capacity.…”

Immunity to gastrointestinal nematode infections

“…33 TSLP can be directly recognized by dendritic cells 54 as well as basophils, 55 again suggesting that epithelial-derived cytokines can bypass ILC2. Indeed, although the main target of IL-25, IL-33, and TSLP appear to be ILC2, it should be noted that both murine and human memory T cells are strongly activated by IL-25, 41,53 IL-33, 53,56,57 and TSLP, 53,58 without the need for T-cell receptor engagement, 57,59 thus being able to respond to antigen nonspecifically. Hence, it remains to be determined what the target cells are for these cytokines, and whether ILCs are truly critical for antiparasitic immunity in previously challenged hosts.…”

Divergent behavior of mucosal memory T cells

“…Cytokines such as IL-7, IL-15, TL1A, and ISG15 have also been reported to elicit immediate IFN-γ production from different populations of effector or memory CD4 or CD8 T cells 16–19 . Holmkvist et al, extend these observations to show that memory T cell exposure to IL-15 and/or TL1a, dramatically enhances cytokine production elicited by IL-12 and IL-18 10 . Importantly, this enhancing effect was observed across a wide range of T cell-derived effector cytokines, including IFN-γ, TNF-α, IL-5, IL-6, IL-13, IL-22, and GM-CSF, suggesting that cytokine-induced cytokine production is not restricted to any individual effector response.…”

“…Holmkvist et al, describe a population of human memory CD4 T cells that express IL-18Rα and DR3 and produce multiple cytokines if exposed to a cocktail of IL-12, IL-18, IL-15, and the DR3 ligand, TL1a 10 . It has long been appreciated that memory T cells secrete effector cytokines in response to other cytokines, and IL-18 was originally termed IGIF (Interferon Gamma-Inducing Factor) in recognition of the capacity to induce IFN-γ production from NK cells and Th1 cells 11, 12 .…”