A New Dynamic Model of CD8+ T Effector Cell Responses via CD4+ T Helper-Antigen-Presenting Cells

Abstract

A long-standing paradox in cellular immunology has been the conditional requirement for CD4+ Th cells in priming of CD8+ CTL responses. We propose a new dynamic model of CD4+ Th cells in priming of Th-dependent CD8+ CTL responses. We demonstrate that OT II CD4+ T cells activated by OVA-pulsed dendritic cells (DCOVA) are Th1 phenotype. They acquire the immune synapse-composed MHC II/OVAII peptide complexes and costimulatory molecules (CD54 and CD80) as well as the bystander MHC class I/OVAI peptide complexes from the DCOVA by DCOVA stimulation and thus also the potential to act themselves as APCs. These CD4+ Th-APCs stimulate naive OT I CD8+ T cell proliferation through signal 1 (MHC I/OVAI/TCR) and signal 2 (e.g., CD54/LFA-1 and CD80/CD28) interactions and IL-2 help. In vivo, they stimulate CD8+ T cell proliferation and differentiation into CTLs and induce effective OVA-specific antitumor immunity. Taken together, this study demonstrates that CD4+ Th cells carrying acquired DC Ag-presenting machinery can, by themselves, efficiently stimulate CTL responses. These results have substantial implications for research in antitumor and other aspects of immunity.