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H2-M3-Restricted T Cells Participate in the Priming of Antigen-Specific CD4⁺ T Cells¹

Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada

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--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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by a grant from the Cancer Research Society (to H.-S.T.). S.D. is supported by the Natural Sciences and Engineering Council of Canada and the Michael Smith Foundation for Health Research.

² Address correspondence and reprint requests to Dr. Hung-Sia Teh, Department of Microbiology and Immunology, Life Sciences Centre, University of British Columbia, Room 3509, 2350 Health Sciences Mall, Vancouver V6T 1Z3, British Columbia, Canada. E-mail address: teh{at}interchange.ubc.ca

³ Abbreviations used in this paper: DC, dendritic cell; LLO, listeriolysin O; LM, Listeria monocytogenes; LCMV, lymphocytic choriomeningitis virus.

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