THE EFFECT OF ANTIGEN DOSE ON CD4(-HELPER CELL PHENOTYPE DEVELOPMENT IN A T-CELL RECEPTOR-ALPHA-BETA-TRANSGENIC MODEL() T)

The dose of foreign antigen can influence whether a cell-mediated or h umoral class of immune response is elicited, and this may be largely a ccounted for by the development of CD4(+) T helper cells (Th) producin g distinct sets of cytokines. The ability of antigen dose to direct th e development of a Th1 or Th2 phenotype from naive CD4(+) T cells, how ever, has not been demonstrated. In this report, we show that the anti gen dose used in primary cultures could directly affect Th phenotype d evelopment from naive D011.10 TCR-alpha beta-transgenic CD4(+) T cells when dendritic cells or activated B cells were used as the antigen-pr esenting cells. Consistent with our previous findings, midrange peptid e doses (0.3-0.6 mu M) directed the development of Th0/Th1-like cells, which produced moderate amounts of interferon gamma (IFN-gamma). As t he peptide dose was increased, development of Th1-like cells producing increased amounts of IFN-gamma was initially observed. At very high ( >10 mu M) and very low (<0.05 mu M) doses of antigenic peptide, howeve r, a dramatic switch to development of Th2-like cells that produced in creasing amounts of interleukin 4 (IL-4) and diminishing levels of IFN -gamma was observed. This was true even when highly purified naive, hi gh 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 dev elopment of this Th2-like phenotype at both high and low antigen doses , demonstrating a requirement for endogenous IL-4. Our findings sugges t that the antigen dose may affect the levels of endogenous cytokines such as IL-4 in primary cultures, resulting in the development of dist inct Th cell phenotypes.