Control of CD4+ T cell responses by γδ T-APCs

Doctoral thesis English OPEN
Tyler, Christopher J. (2016)
  • Subject: QR180 | R1

Human Vγ9Vδ2 T cells constitute a novel type of APC (γδ T-APCs) capable of stimulating CD4+ T cell responses. The outcome of γδ T-APC induced CD4+ T cell responses in terms of cytokine profiles, and the physiological implications for infection and autoimmunity, remain unknown. This study demonstrates that γδ T cells are able to act as potent APCs, inducing proliferation in naive and memory CD4+ T cell populations. Resulting cytokine responses triggered in naive CD4+ T cells included production of IFN-γ and IL-22. Of note, γδ T cells had a greater capacity to promote production of IL-22 in naive and memory T cells than monocytes and monocyte-derived DCs in identical experiments. The microenvironment of γδ T-APCs played a major role in the subsequent polarisation of CD4+ T cell responses, with APCs induced in the presence of IL-15 being superior in promoting IL-22 responses in naive CD4+ T cells compared to γδ T-APCs generated in the presence of other cytokines. Unexpectedly, the IL-22 induction in CD4+ T cells was IL-6 independent, but instead involved TNF-α and ICOS-L, both expressed by the γδ T-APCs. In addition, γδ T-APCs induced in the presence of IL-21 favoured increased induction of IL-10 in CD4+ T cells. The observation that γδ T-APCs are able to drive IL-22 responses in naive and memory T-cell populations presents a novel function for these APCs, with implications for a multitude of infection/disease scenarios. One such scenario is Inflammatory Bowel Disease (IBD), where IL-22 and γδ T-cells have previously been shown to play significant roles in disease pathogenesis and progression. Indeed, γδ T cells derived from intestinal biopsies are able to act as fully functional APCs. In summary, γδ T-APCs may be involved in the pathogenesis or maintenance of autoimmune inflammation in the intestine and other peripheral sites.
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