Differential activation of CD8+ T cells by transforming growth factor-beta 1.

Transforming growth factor-beta (TGF-beta) is a highly conserved multifunctional factor that broadly regulates cell growth and differentiation, and exhibits diverse regulatory roles in the immune system. In contrast to other studies describing TGF-beta as a potent inhibitor of lymphocyte growth, we have shown previously that TGF-beta 1 can also costimulate proliferation of murine splenic T cells activated by immobilized anti-CD3 antibody. In the present studies, we further investigate the subsets of T cells that are responsive to TGF-beta 1 costimulation. T cells were isolated into CD45RBhi/lo or CD4+/8+ populations, and their responses to TGF-beta 1 were examined. Sorted CD45RBhi cells were highly responsive to TGF-beta 1 costimulation, and proliferated to a level similar to that of unsorted T cells in response to TGF-beta 1. TGF-beta 1 also costimulated proliferation in the CD45RBlo population that was distinguished by low response and delayed kinetics. In contrast, sorted CD4+ and CD8+ T cells showed a striking differential response. Anti-CD3-stimulated proliferation of sorted CD8+ or CD4- T cells was substantially enhanced by TGF-beta 1, whereas sorted CD4+ or CD8- T cells were unresponsive. TGF-beta 1 also down-regulated CD45RB and increased CD44 expression on responsive CD8+ and CD45RBhi T cells, thereby leading to a population of T cells enriched in mature phenotype. Generation of anti-CD3-redirected lytic activity by these TGF-beta 1-costimulated CD8+ cells was strongly suppressed. However, these CD8+ T cells exhibited cytotoxic activity after restimulation in the absence of TGF-beta. TGF-beta 1 precultured CD8+ T cells also had heightened IL-2 and IFN-gamma secretion upon restimulation in comparison to cells activated initially without TGF-beta. CD8+ T cells precultured with anti-CD3 and TGF-beta remained responsive to growth enhancement by TGF-beta, although re-exposure to TGF-beta depressed other functions of these cells. Thus, TGF-beta 1 demonstrates important costimulatory roles in both growth and maturation of CD8+ T cells.