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Emergence of Regulatory CD4⁺ T Cell Response to Repetitive Stimulation with Antigen-Presenting Cells In Vitro: Implications in Designing Antigen-Presenting Cell-Based Tumor Vaccines¹

Nitya G. Chakraborty^2,*, Li Li^*, Jonathan R. Sporn^*, Scott H. Kurtzman, M. T. Ergin and Bijay Mukherji^*

Departments of ^* Medicine and Surgery, University of Connecticut School of Medicine, Farmington, CT 06030

Because APCs play a crucial role in the generation of T cell-mediated immune responses, numerous clinical trials with APC-based vaccines have been initiated in different types of human cancers. Encouraging results have emerged from some of these initial studies. Thus far, APC-based vaccinations usually include multiple rounds of immunization. With this approach, although we and others have detected induction of Ag-specific CTL responses in vaccinated patients after stimulation with the same APC-based immunogen, in vitro we also find that repetitive in vitro stimulation with Ag-loaded APC can, at times, lead to the emergence of noncytolytic CD4⁺ T cells exhibiting the characteristic phenotype of Th2 cells. These noncytolytic CD4⁺ T cells synthesize large quantities of type 2 cytokines such as IL-4 and IL-10 on stimulation with the autologous APC or tumor cells in an MHC class II-restricted manner. Further, these CD4⁺ T cells and a cell-free supernatant factor block the activation of fresh T lymphocytes. The supernatant factor also exhibits a marked inhibitory effect on the expression of the costimulatory molecules, CD80 and CD86, by APC. The inhibitory effect of the supernatant factor can be abrogated by neutralizing IL-10 in the supernatant. These observations therefore have implications in the APC-based tumor vaccine protocol design.

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