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Inhibition of Cytolytic T Lymphocyte Proliferation by Autologous CD4⁺/CD25⁺ Regulatory T Cells in a Colorectal Carcinoma Patient Is Mediated by Transforming Growth Factor-ß¹

The Wistar Institute, Philadelphia, Pennsylvania 19104 [R. Som., L. J., R. Swo., L. C., H. S., S. B., D. P., D. C., B. B., J. K., K. B., D. H.]; Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104 [D. M.]; National Cancer Institute, Bethesda, Maryland 20892 [F. M.]; and Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [E. B., M. M.]

Cancer patients often develop CTLs that lyse autologous tumor cells in culture. However, tumors can progress in vivo despite the presence of CTLs. Various mechanisms have been reported to down-modulate CTL functions. In this study, the role of CD4⁺/CD25⁺ regulatory T cells in CTL induction and proliferation of established CTLs was investigated in a patient with CRC. CD4⁺ cytotoxic and regulatory T-cell lines were derived from the peripheral blood mononuclear cells of the same patient in mixed-lymphocyte tumor culture. The cytotoxic T-cell line and a clonal derivative specifically lysed the autologous tumor cells but not the B lymphocytes. Only HLA-A1-matched allogeneic CRC cells were lysed by the CTL clone. The clone produced IFN- and TNF-. The regulatory CD4⁺/CD25⁺ T-cell line was tumor cell-dependent in its growth but did not lyse autologous tumor cells. This T-cell line suppressed pokeweed mitogen responses of allogeneic lymphocytes, proliferative activity of the established, autologous CTLs, and induction of CTLs in autologous, freshly isolated peripheral blood mononuclear cells. The immunosuppressive effect of the CD4⁺/CD25⁺ regulatory T cells was mediated by transforming growth factor-ß and did not require cell-to-cell contact. Thus, although CRC patients can develop specific CTLs against their tumors, the development of regulatory T cells may allow the escape of tumor cells from immune surveillance by the CTLs in vivo.

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