The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model.

TLDR

The dose of foreign antigen can determine whether a cell‑mediated or humoral immune response is elicited, largely through the development of CD4⁺ T helper cells that produce distinct cytokine profiles. The study demonstrates that antigen dose directly influences Th phenotype development from naive CD4⁺ T cells in a transgenic model using dendritic or B‑cell antigen presentation. Mid‑range peptide doses (0.3–0.6 µM) induced Th0/Th1‑like cells producing moderate IFN‑γ, whereas very low (<0.05 µM) or very high (>10 µM) doses switched development to Th2‑like cells producing IL‑4 and reducing IFN‑γ; neutralizing IL‑4 blocked this switch, indicating IL‑4 drives the dose‑dependent Th phenotype selection.

Abstract

The dose of foreign antigen can influence whether a cell-mediated or humoral class of immune 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 Th1 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 DO11.10 TCR-alpha beta-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 microM) directed the development of Th0/Th1-like cells, which produced moderate amounts of interferon gamma (IFN-gamma). As the peptide dose was increased, development of Th1-like cells producing increased amounts of IFN-gamma was initially observed. At very high (&amp;gt; 10 microM) and very low (&amp;lt; 0.05 microM) doses of antigenic peptide, however, a dramatic switch to development of Th2-like cells that produced increasing amounts of interleukin 4 (IL-4) and diminishing levels of IFN-gamma was observed. This was true even when highly purified naive, high buoyant density CD4+ LECAM-1hi 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 Th2-like 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.