γδ T Cells' Role in Donor-Specific Antibody Generation: Insights From Transplant Recipients and Experimental Models

The generation of donor-specific antibodies (DSA) requires that alloreactive B cells receive help from follicular helper T (T_FH) cells. Recent works have suggested that γδ T cells could contribute to T cell-dependent humoral responses, leading us to investigate their role in DSA generation. Analysis of a cohort of 331 kidney transplant recipients found no relation between the number of circulating γδ T cells and the risk to develop DSA. Coculture models demonstrated that activated γδ T cells were unable to promote the differentiation of B cells into plasma cells, ruling out that they can be "surrogate" T_FH. In line with this, γδ T cells preferentially localized outside the B cell follicles, in the T cell area of lymph nodes, suggesting that they could instead act as "antigen-presenting cell" (APC) to prime αβ T_FH. This hypothesis was proven wrong since γδ T cells failed to acquire APC functions in vitro. These findings were validated in vivo by the demonstration that following transplantation with an allogeneic Balb/c (H2^d) heart, wild-type and TCRδKO C57BL/6 (H2^b) mice developed similar DSA responses, whereas TCRαKO recipients did not develop DSA. We concluded that the generation of DSA is unfazed by the absence of γδ T cells.