n t in a T Cell Receptor - oL [ 3 - transgenic

The dose of foreign antigen can influence whether a cell-mediated or humoral class ofirm'nune response is elicited, and this may be largely accounted for by the development of CD4 + T helper cells (Th) producing distinct sets of cytokines. The ability of antigen dose to direct the development of a Thl or Th2 phenotype from naive CD4 + T cells, however, has not been demonstrated. In this report, we show that the antigen dose used in primary cultures could directly affect Th phenotype development from naive DOl1.10 TCR-et[3-transgenic CD4 + T cells when dendritic cells or activated B cells were used as the antigen-presenting cells. Consistent with our previous findings, midrange peptide doses (0.3-0.6 p,M) directed the development of Th0/Thll ike cells, which produced moderate amounts of interferon ~/ (IFN-y). As the peptide dose was increased, development of Thl-like cells producing increased amounts of IFN-'y was initially observed. At very high (>10 p,M) and very low (<0.05 b~M) doses of antigenic peptide, however, a dramatic switch to development of Th2-1ike cells that produced increasing amounts of interleukin 4 (IL-4) and diminishing levels of IFN-y was observed. This was true even when highly purified naive, high buoyant density CD4 + LECAM-1 hi T cells were used, ruling out a possible contribution from contaminating "memory" phenotype CD4 + T cells. Neutralizing anti-IL-4 antibodies completely inhibited the development of this Th2like phenotype at both high and low antigen doses, demonstrating a requirement for endogenous IL-4. Our findings suggest that the antigen dose may affect the levels of endogenous cytokines such as IL-4 in primary cultures, resulting in the development of distinct Th cell phenotypes.