Natural antibodies and complement are endogenous adjuvants for vaccine-induced CD8+ T-cell responses

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Abstract

CD8+ T cells are essential for long-term, vaccine-induced resistance against intracellular pathogens. Here we show that natural antibodies, acting in concert with complement, are endogenous adjuvants for the generation of protective CD8+ T cells after vaccination against visceral leishmaniasis. IL-4 was crucial for the priming of vaccine-specific CD8+ T cells, and we defined the primary source of IL-4 as a CD11b+CD11clo phagocyte. IL-4 secretion was not observed in antibody-deficient mice and could be reconstituted with serum from normal, but not Btk immune-deficient, mice. Similarly, no IL-4 response or CD8+ T-cell priming was seen in C1qa−/− mice. These results identify a new pathway by which immune complex–mediated complement activation can regulate T-cell-mediated immunity. We propose that this function of natural antibodies could be exploited when developing new vaccines for infectious diseases.

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Figure 1: IL-4 is required for vaccination against leishmaniasis.
Figure 2: Priming of recombinant HASPB1–specific CD8+ T cells requires IL-4.
Figure 3: IL-4 secretion is upstream of IL-12 production.
Figure 4: CD11b+CD11clo phagocytes are responsible for primary IL-4 secretion.
Figure 5: IL-4 secretion requires immune complexes.
Figure 6: Cytokine secretion and CD8+ T-cell priming are complement-dependent.

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Acknowledgements

This work was supported by the British Medical Research Council and The Wellcome Trust. Clodronate and control liposomes were a gift of Roche Diagnostics. The authors thank J. Langhorne (National Institute for Medical Research) for CBA/N serum, H. Helmby (London School of Hygiene and Tropical Medicine) for ACK2 monoclonal antibody, M. Ato for critical comments on the manuscript, the staff of the Biological Services Facility for animal husbandry and Joanne Warren for technical assistance. F.B. holds a Wellcome Trust Research Senior Fellowship for Medical Science in South Africa (grant no. 056708/Z/99).

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Correspondence to Paul M Kaye.

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S.S., D.F.S. and P.M.K. are named inventors on a patent application covering the use of natural antibodies to screen pathogen proteomes for new vaccine candidates (UK Patent Application 03006616.4).

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