PD-1 deficiency promotes TFH cells expansion in ITV-immunized mice by upregulating cytokines secretion.

BACKGROUND

T follicular helper (TFH) cells are fundamental for the development of humoral immunity. In our previous study, we found that PD-1 deficiency substantially promoted the expansion of Plasmodium-specific TFH cells and enhanced the humoral immunity of ITV (infection treatment vaccine)-immunized mice. However, the underlying mechanism by which PD-1 signaling modulates TFH cells activation remains unclear.

METHODS

Mice were immunized with the ITV following the standard procedures. The activation phenotype of CD11cCXCR5 dendritic cells (DCs), the frequency and number of splenic follicular regulatory T cells (TFR cells), Plasmodium-specific TFH cells and germinal center (GC) B cells were analyzed by FACS. The levels of serum cytokines were quantified using the cytometric bead array (CBA) and in vivo cytokine neutralization was carried out according to a previously described protocol and verified by serum cytokine detection.

RESULTS

We found that PD-1 naïve and immunized mice had more TFR cells in the spleen than WT and WT immunized mice. Additionally, CXCR5 DC, which prime TFH cells, were activated at similar levels in ITV-immunized WT and PD-1 mice. However, the serum levels of IL-10, IFN-γ and MCP-1 were significantly increased in ITV-immunized PD-1 mice, and treatment with an anti-IL-10, anti-IFN-γ or anti-MCP-1 neutralizing antibody in vivo markedly impaired the development of TFH cells and GC B cells.

CONCLUSIONS

Our findings demonstrate that the modulation of TFH cells by PD-1 signaling is dependent on the cytokines IL-10, IFN-γ and MCP-1 in ITV-immunized mice. These results could facilitate the design of an effective malaria vaccine with the aim of inducing humoral immune responses.