GENERATION OF POLARIZED ANTIGEN-SPECIFIC CD8 EFFECTOR POPULATIONS - RECIPROCAL ACTION OF INTERLEUKIN (IL)-4 AND IL-12 IN PROMOTING TYPE-2 VERSUS TYPE-1 CYTOKINE PROFILES

We have generated primary effector populations from naive CD8 T cells in response to antigen and determined their patterns of cytokine secretion upon restimulation. The effect of exogenous factors on the effector generation was examined and compared with responses of antigen-specific CD4 effecters generated under comparable conditions. CD8 cells from bm1 mice were stimulated with C57BL/6 (B6) antigen presenting cells (APCs) bearing allogeneic class I and CD8 cells from female severe combined immunodeficiency (SCID) B6 mice, transgenic for a T cell receptor alpha/beta (TCR-alpha/beta)that recognizes H-Y on D-b, were stimulated with APCs from male mice. In parallel, CD4 cells from bm12 mice were stimulated with alloantigen and CD4 cells from V beta 3/V alpha 11 TCR transgenics were stimulated with a peptide of pigeon cytochrome c on IE(k). T cells from both transgenic mice were of naive phenotype whereas normal mice contained 10-20 % memory cells. Effector CD8 populations generated were L-selectin low, CD45RB high, and CD44 high. Naive CD8 cells from SCID anti-H-Y mice made little or no cytokine immediately upon stimulation in contrast to naive CD4 which produced large amounts of interleukin 2 (IL-2). Both populations, however, generated primary effecters over 4-5 d that made substantial quantities of many cytokines upon restimulation. Both CD8 and CD4 effecters produced similar patterns of cytokines with alloantigen or specific antigen. Cytokines present during naive CD8 stimulation influenced the cytokine secretion profile of the effecters, as previously shown for CD4 cells, although secretion by CD8 effecters was generally lower than that of CD4 effecters. CD8 cells cultured with IL-2 alone made predominantly interferon gamma (IFN-gamma) and no IL-4 or IL-5, similar to CD4 cells. Priming with IFN-gamma increased IFN-gamma secretion from CD4 effecters, but had little if any effect on CD8 cells. In contrast, priming with IL-12 generated CD8 effecters, as well as CD4 effecters, producing elevated quantities of IFN-gamma, with similar levels from both the CD4 and CD8 populations. The presence of IL-4 during effector cell generation promoted synthesis of IL-4 and IL-5 from both CD8 and CD4 cells while downregulating IFN-gamma secretion. CD8 cells made only small amounts of IL-4, more than 100-fold less than CD4 cells, whereas significant levels of IL-5 were induced, only 3-10-fold lower than from CD4. Thus there are strong similarities between CD8 and CD4 T cells in the development of primary effector populations, but some key differences. We predict that the polarized subsets of CD8 effector T cells will be found to play different roles in the immune response.