H2-M3-Restricted T Cells Participate in the Priming of Antigen-Specific CD4+ T Cells

H2-M3-restricted CD8 + T cells provide early protection against bacterial infections. In this study, we demonstrate that activated H2-M3-restricted T cells provide early signals for efficient CD4 + T cell priming. C57BL/6 mice immunized with dendritic cells coated with the MHC class II-restricted listeriolysin O peptide LLO 190–201 (LLO) generated CD4 + T cells capable of responding to Listeria monocytogenes (LM) infection. Inclusion of a H2-M3-restricted formylated peptide fMIGWII (fMIG), but not MHC class Ia-restricted peptides, during immunization with LLO significantly increased IFN-γ-producing CD4 + T cell numbers, which was associated with increased protection against LM infection. Studies with a CD4 + T cell-depleting mAb indicate that the reduction in bacterial load in fMIG plus LLO immunized mice is likely due to augmented numbers of LLO-specific CD4 + T cells, generated with the help of H2-M3-restricted CD8 + T cells. We also found that augmentation of LLO-specific CD4 + T lymphocytes with H2-M3-restricted T cells requires presentation of LLO and fMIG by the same dendritic cells. Interestingly, the augmented CD4 + T cell response generated with fMIG also increased primary LM - specific responses by MHC class Ia-restricted CD8 T cells. Coimmunization with LLO and fMIG also increases the number of memory Ag-specific CD4 + T cells. We also demonstrate that CD8 T cells restricted to another MHC class Ib molecule, Qa-1, whose human equivalent is HLA-E, are also able to enhance Ag-specific CD4 + T cell responses. These results reveal a novel function for H2-M3- and Qa-1-restricted T cells; provision of help to CD4 + Th cells during the primary response.