CD40-independent pathways of T cell help for priming of CD8(+) cytotoxic Tlymphocytes

In many cases, induction of CD8(+) CTL responses requires CD4(+) T cell hel p. Recently, it has been shown that a dominant pathway of CD4(+) help is vi a antigen presenting cell (APC) activation through engagement of CD40 by CD 40 ligand on CD4(+) T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and i nfluenza hemagglutinin (HA) class I and II peptide-specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4(+) T helper cells, respectively. We found that CD4(+) T cells can provide pot ent help for DCs to activate CD8(+) T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Su rprisingly, this help is completely independent of CD40. Moreover, CD40-ind ependent CD4(+) help can be documented in vivo. Finally, we show that CD40- independent T cell help is delivered through both sensitization of DCs and direct CD4(+)-CD8(+) T cell communication via lymphokines. Therefore, we co nclude that CD4(+) help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine -dependent CD4(+)-CD8(+) T cell communication.