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Novel antigens for human gamma delta T cells

Final Report Summary - NOVAGAMD (Novel antigens for human gamma delta T cells)

Because optimal organ function is key to the survival of metazoan organisms, the maintenance of tissue integrity via immunosurveillance is likely to involve multiple components. One of these is formed by populations of unconventional T cells that include NKT cells and gamma delta T cells. Whereas conventional lymphocytes make responses that are delayed by the time taken to expand relevant clones, gd T lymphocytes can respond very rapidly to infectious or non-microbial stress. While an increasing number of papers define critical contributions of gamma delta T cells to host protection against infections and malignancy, progress in the field is confounded by our ignorance of the antigens for most gamma delta T cell receptors (TCR). Identifying such ligands provides insight into TCR biochemistry (and how it differs from alpha beta TCR biochemistry) and the biology of cell recognition by gamma delta T cells. This information can identify pathways common to cell infection and cell transformation, in which 'stress-antigens' are regulated. This can in turn aid the development of clinical strategies to enhance tumour immunology or vaccination.

Most human peripheral blood gamma delta T cells express a Vgamma9/Vdelta2-TCR. However, there is much interest in human gamma delta T cells that do not express this receptor, in part because these Vgamma9/Vdelta2-negative cells are commonly associated with tissues where they may participate in the first line of stress-surveillance. Recently, together with collaborators, our lab established a set of Vgamma9/Vdelta2-negative clones from Cytomegalovirus (CMV)-infected, immunosuppressed transplant patients that react to certain colon tumours and to CMV-infected cells (Halary et al., 2005). One of these clones has been found to bind the endothelial cell protein C receptor (EPCR) via its TCR. This is crucial in preventing blood coagulation through the activation of protein C, a natural anticoagulant protease (Willcox et al., 2012).

In order to assess the generality of EPCR reactivity, we undertook an analysis of gamma/delta T cells from many healthy donors, adult and neonates. We found that none of the multiple gamma/delta T cell populations tested recognised EPCR, which suggests a diversified TCR-dependent adaptive response of Vdelta2neg gd T cells.

Moreover, our observation that costimulatory molecules were implicated in EPCR-dependent recognition of CMV-infected cells led us to hypothesise that these molecules are crucial for the adaptive potentials of gd T cells. Therefore, in order to identify new antigens for gd T cells, we focused our effort on attempts to identify new costimulatory elements necessary for gd TCR reactivity. We discovered that IL-7 promotes strong responses of IL-17-producing gd cells to TCR agonists. In mouse, IL-17-producing gd cells (mainly Vgamma4+) are widely viewed as innate since they are rapidly activated by IL-1 and IL-23 alone and are relatively unresponsive to TCR agonists that strongly activate IFN-gamma-producing gd cells. However, we revealed that IL-7 selectively facilitates strong responses of IL-17-producing gd cells to TCR stimulation whether measured by expansion, activation markers, or effector function. Concerning human, IL-17-producing Vdelta1+ and Vdelta2+ cells are also substantially expanded by IL-7 plus TCR agonists. These findings highlight IL-7 as a novel and important regulator of gd cells' adaptive properties and justifies our ongoing studies into the identification of new gdTCR ligands associated with costimulatory elements.