Heterogeneous mechanisms of human cytotoxic T lymphocyte generation. II. Differential effects of IL-6 on the helper cell-independent generation of CTL from CD8+ precursor subpopulations.

The subpopulations of CD8+ T cells defined by CD45RA Ag expression have been hypothesized to represent cells varying in their relative maturation along a common, activation-dependent differentiation pathway. Although both the CD8+CD45RA+ and CD8+CD45RA- subsets contain precursor cells that can develop into alloreactive CTL, these subsets differ in their ability to produce and use IL-2, a cytokine that is essential for T helper cell-independent CTL generation. In these studies, we have characterized the ability of these CD8+ subsets to undergo CTL differentiation in response to IL-6, another cytokine reported to be important or even essential for CTL generation. Purified CD8+CD45RA+ or CD8+CD45RA- cells were stimulated with allogeneic B cell lines, either alone or in the presence of exogenous cytokines. Alloactivated CD8+CD45RA- cells failed to differentiate into cytotoxic cells in the presence of IL-6 alone. In contrast, IL-6 stimulated the differentiation of antigen-specific CTL from alloactivated CD8+CD45RA+ precursors. The mechanism underlying this helper cell-independent process appeared to require IL-2, because IL-6-mediated CTL generation was abrogated by anti-CD25 or anti-IL-2 antibodies. Although CD8+CD45RA- cells did not respond to IL-6 alone, these cells were able to respond to IL-6 in a synergistic fashion in the presence of suboptimal concentrations of exogenous IL-2. These studies demonstrate that the CD8+ precursor subsets defined by CD45RA expression differ in their ability to undergo IL-6-mediated helper cell-independent CTL generation. Our data further suggest that this functional dissimilarity results from putative maturation-linked differences in the ability of these CD8+ precursor cells to produce IL-2.