CD40-independent pathways of T cell help for priming of CD8⁺ cytotoxic T lymphocytes

In many cases, induction of CD8⁺ CTL responses requires CD4⁺ T cell help. Recently, it has been shown that a dominant pathway of CD4⁺ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 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 influenza 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 potent help for DCs to activate CD8⁺ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent 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 conclude 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.