γδ T cells control humoral immune response by inducing T follicular helper cell differentiation

gamma delta T cells have many known functions, including the regulation of antibody responses. However, how gamma delta cells control humoral immunity remains elusive. Here we show that complete Freund's adjuvant (CFA), but not alum, immunization induces a subpopulation of CXCR5-expressing gamma delta T cells in the draining lymph nodes. TCR gamma delta(+)CXCR5(+) cells present antigens to, and induce CXCR5 on, CD4 T cells by releasing Wnt ligands to initiate the T follicular helper (Tfh) cell program. Accordingly, TCR delta(-/-) mice have impaired germinal center formation, inefficient Tfh cell differentiation, and reduced serum levels of chicken ovalbumin (OVA)-specific antibodies after CFA/OVA immunization. In a mouse model of lupus, TCR delta(-/-) mice develop milder glomerulonephritis, consistent with decreased serum levels of lupus-related autoantibodies, when compared with wild type mice. Thus, modulation of the gamma delta T cell-dependent humoral immune response may provide a novel therapy approach for the treatment of antibody-mediated autoimmunity.