Human Vγ9Vδ2-T Cells Synergize CD4+ T Follicular Helper Cells to Produce Influenza Virus-Specific Antibody

Human V gamma 9V delta 2-T cells recognize nonpeptidic antigens and exert effector functions against microorganisms and tumors, but little is known about their roles in humoral immune response against influenza virus infection. Herein, in the coculture of autologous human B cells, dendritic cells and/or naive CD4 T cells, and V gamma 9V delta 2-T cells, we demonstrated that V gamma 9V delta 2-T cells could facilitate H9N2 influenza virus-specific IgG and IgM productions in a CD4 T cell-dependent manner. V gamma 9V delta 2-T cells promoted the differentiation of CXCR5(+)PD1(+)CD4(+)T follicular helper (Tfh) cells, CD19(+)IgD-CD38(++) plasma cells (PCs), and drove B cell proliferation as well as immunoglobulin class switching. Interestingly, V gamma 9V delta 2-T cells acquired Tfh-associated molecules such as CXCR5, PD1, CD40L, and ICOS during influenza virus stimulation, especially in the presence of CD4 T cells. Moreover, V gamma 9V delta 2-T cells promoted CD4 T cells to secrete IL-13 and IL-21, and neutralizing IL-13 and IL-21 significantly reduced the number of CD19(+)IgD-CD38(++) PCs. Using humanized mice, we further demonstrated that V gamma 9V delta 2-T cells could synergize CD4 T cells to produce influenza virus-specific antibody. Our findings provide a greater scope for V gamma 9V delta 2-T cells in adaptive immunity, especially for the Tfh development and humoral immune responses against influenza virus infection.