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A New Dynamic Model of CD8⁺ T Effector Cell Responses via CD4⁺ T Helper-Antigen-Presenting Cells¹

Research Unit, Saskatchewan Cancer Agency, Departments of Oncology, Microbiology, and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

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 (DC_OVA) 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 DC_OVA by DC_OVA 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.

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