Proinflammatory Vδ2+ T Cells Populate the Human Intestinal Mucosa and Enhance IFN-γ Production by Colonic αβ T Cells

Abstract

In nonhuman primates, Vγ9Vδ2+ (Vδ2)T cells proliferate and accumulate in mucosal tissues following microbial activation. Human Vδ2T cells produce proinflammatory cytokines in response to bacterial species that colonize the gut, but the role played by Vδ2T cells in intestinal immunity is unknown. We hypothesized that circulating Vδ2T cells can populate the human intestine and contribute to mucosal inflammation. Cell suspensions prepared from peripheral blood and intestinal biopsies were stimulated with microbial phosphoantigen (1-hydroxy-2-methyl-2-buten-4-yl 4-diphosphate [HDMAPP]) and analyzed by flow cytometry to determine Vδ2T cell phenotype, cytokine production, and proliferative potential. Circulating Vδ2T cells expressed gut-homing integrin α4β7 (>70%), which was coexpressed with skin-associated cutaneous leukocyte Ag by up to 15% of the total population. However, Vδ2T cell activation with HDMAPP and exposure to retinoic acid (signaling via retinoic acid receptor α) increased α4β7 expression and enhanced binding to mucosal addressin cell adhesion molecule-1 in vitro while simultaneously suppressing cutaneous leukocyte Ag, thereby generating a committed gut-tropic phenotype. Confocal microscopy and flow cytometry identified frequent Vδ2T cells that migrated out of human intestinal biopsies and comprised both CD103+ and CD103− subsets that produced TNF-α and IFN-γ upon phosphoantigen exposure, with more frequent cytokine-producing cells in the CD103− population. Activated intestinal Vδ2T cells expressed CD70 and HLA-DR but were unable to drive the proliferation of allogeneic naive CD4+ T cells. Instead, phosphoantigen-activated CD103− Vδ2T cells increased T-bet expression and enhanced IFN-γ production by autologous colonic αβ T cells via an IFN-γ–dependent mechanism. These data demonstrate that circulating Vδ2T cells display enhanced gut-homing potential upon microbial activation and populate the human intestinal mucosa, generating functionally distinct CD103+ and CD103− subsets that can promote inflammation by colonic αβ T cells.

Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

“…These data indicate a potential role for Vδ2 T cells in the pathology of Crohn's disease (CD), which is characterized by enhanced effector function of CD4 + T cells directed against components of the gut microbiota. In addition to our own detection of Vδ2 T cells in human colonic lamina propria in situ (11), these cells have also been observed in gastrointestinal lymphoid tissues (12) and were previously identified in the gut in a small number of CD patients (13,14), but the role played by these cells in mucosal inflammation in CD is currently unknown.…”

“…Vδ2 T cells are unconventional blood lymphocytes that are uniquely able to recognize PAg produced by tumor cells and microbes (1,5,6). We recently demonstrated that PAg exposure stimulates human blood Vδ2 T cells to upregulate the gut-homing integrin α4β7 and increase binding to the intestinal addressin MAdCAM-1 (11). To test the hypothesis that human Vδ2 T cells contribute to mucosal inflammation in CD, we first used flow-cytometry to assess the gut-homing potential of blood Vδ2 T cells in a cohort of CD patients who had moderately active disease but who were not receiving immunosuppressive therapy.…”

“…Intriguingly, human patients with mutations in the mevalonate kinase gene exhibit a severe neonatal colitis that can be successfully treated with bisphosphonate drugs, which modulate PAg synthesis and alter Vδ2 T cell function in vivo (7)(8)(9)(10). We recently reported that PAg exposure stimulates human blood Vδ2 T cells to upregulate the gut-homing integrin α4β7, and we identified Vδ2 T cells in human colonic biopsies that produced proinflammatory cytokines and enhanced IFNγ synthesis by intestinal CD4 + T cells (11). These data indicate a potential role for Vδ2 T cells in the pathology of Crohn's disease (CD), which is characterized by enhanced effector function of CD4 + T cells directed against components of the gut microbiota.…”

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…As a flip side of the potential benefit of the adjuvant properties of Vc9/Vd2 T cells, a dysregulated generation of APCs under the influence of Vc9/Vd2 T cells may eventually result in uncontrolled inflammation and the generation of cellular and humoral autoimmune responses, thereby contributing to the clinical symptoms in scenarios such as psoriasis [226], inflammatory bowel disease [227], celiac disease [196,228], and multiple sclerosis [229]. More research is clearly needed to delineate the complex interactions of Vc9/Vd2 T cells (and other unconventional T cells) with different immune and non-immune cells, both locally and systemically, and define how such knowledge can be exploited for therapeutic interventions to either boost protective immune responses or suppress excessive inflammation.…”

Modulation of T Cell and Innate Immune Responses by Retinoic Acid

“…This provides further evidence that RA can have direct and indirect effects on CD4 + effector T cells. Studies in humans (84) showed that the RA-RARa pathway induces expression of the gut-homing integrin a4b7 and its ligand addressin (MAdCAM-1) on circulating Vd2…”