Antigen dose differentially controls the induction of specific Treg and Teff populations (49.5)

Abstract

Abstract The concept that Th1/Th2 differentiation may be affected by antigen dose was introduced a decade ago (O’Garra, Bottomly). Recently, we reported that antigen dose also controls Treg induction whereby low antigen doses elicit weak signals via the TCR/Akt/mTOR pathway, allowing Foxp3 expression and expansion of Treg. METHODS: We expanded our studies on antigen dose effects to include regulatory and effector populations that have been recently added to the CD4+ repertoire. Purified CD4+ T cells from BDC2.5 TCR transgenic mice were stimulated by DC pulsed with increasing doses of peptide antigen. After 7 days of priming, T cells were re-stimulated with anti-CD3 and anti-CD28 and analyzed for cytokine production and Foxp3 expression. RESULTS: We found that altering the antigen dose qualitatively affected the CD4+ T cell response in a hierarchical manner. Low dose stimulation led to Foxp3+ Treg expansion; intermediate doses induced IL-13+ Th2 and IL-10+ Tr1 cells; and higher antigen doses favored Th1/Th17 responses. In addition, when low-dose-stimulated T cells were subsequently re-stimulated with a high antigen dose, the Th1/Th17 response remained diminished. CONCLUSIONS: Our results indicate that Tr1, Th17 and Treg are included in the repertoire of CD4+ T cells that are affected by antigen dose. These findings have broad implications for vaccine design and we are in the process of determining the in vivo significance of these qualitative changes to the CD4 compartment.