Role of human V[gamma]9V[delta]2 T cells in the production of influenza virus-specific antibodies in vitro and in vivo

Abstract

Influenza virus causes endemics and occasionally global outbreaks, which pose a significant threat to human health. Vaccination induced antigen-specific antibodies play an essential role in the protection against influenza virus infection in human. Vγ9Vδ2 T cells constitute 1-5% of circulating T cells in human peripheral blood and they can be expanded rapidly in response to microbes that produce the metabolite pyrophosphate. Vγ9Vδ2 T cells showed profound cytotoxic activity to infected cells, infectious pathogens or tumor cells. More recent studies in human indicated that Vγ9Vδ2 T cells exhibited follicular helper T (Tfh) cell features after phosphoantigen and IL-21 treatment, and these Tfh-like Vγ9Vδ2 T cells could provide B cell help for antibody production in vitro. However, it is still unknown whether Vγ9Vδ2 T cells can enable B cells produce antigen-specific antibodies and the combinational role of Vγ9Vδ2 T cells and CD4 T cells in the humoral response against influenza virus stimulation. In vitro study, we demonstrated that Vγ9Vδ2 T cells could facilitate influenza virusspecific antibodies production in a CD4 T cell-dependent manner, as indicated by the significantly virus-specific IgG and IgM in CD4 T- Vγ9Vδ2 T group compared with CD4-T group. In our co-culture system, Vγ9Vδ2T cells acquired large amounts of Tfh-associated markers such as CXCR5, PD1, CD40L, ICOS, and OX40 when cultured with B cells as well as CD4 T cells. Interestingly, these Tfh-like Vγ9Vδ2T cells also promote CD4 Tfh cell differentiation, as represented by the up-regulated frequency of CXCR5+Bcl6+CD4+ and CXCR5+PD1+CD4+ T cells. The reciprocal effect between Vγ9Vδ2 T and CD4 T cells in the differentiation of Tfh cells could be reflected on the plasma cell differentiation. We identified a significant up-regulated population of CD3-CD19+IgD-CD38++ plasma cells when Vγ9Vδ2T cells and CD4 T cells were co-cultured. Besides, Vγ9Vδ2 T cells enabled CD4 T cells to produce more IL-13 and IL-21 during plasma cell differentiation. My in vivo studies that applied humanized mice also confirmed the result that Vγ9Vδ2 T cells could facilitate virus-specific antibody production in a CD4 T cellsdependent manner. Therefore, we provide both in vitro an in vivo evidence to indicate to role of Vγ9Vδ2 T cells in the generation of influenza virus antigen-specific antibody. This study also gives a great scope of Vγ9Vδ2 T cells to improve the influenza virus specific-antibody generation efficiency.