Different requirements for CD40-DC154 interaction during thymic negative selection of CD4+ T cells

Abstract

Rationale Self-reactive T cells are normally deleted in the thymus through negative selection. In addition to TCR engagement, negative selection is regulated by signals from co-stimulatory molecules, particularly CD154. Previous research has demonstrated negative selection to endogenously expressed antigens is dependent on CD40-CD154 interactions while negative selection to exogenously administered antigen is independent of CD154. Methods Transgenic animals from two different models of thymic negative selection were injected with mAb to CD154 or control antibody. Following treatment, cell populations were analyzed by flow cytometry. Results In this study we found differential effects of CD154 blockade on two different models of CD4+ T cell negative selection to endogenously expressed self-antigens. Treatment with anti-CD154 mAb resulted in accumulation of large numbers of functional auto-reactive T cells in the thymus of ANDxRO Tg animals. However, these animals had few transgenic cells in the periphery and the remaining few cells had been rendered anergic. In another model of negative selection, Act-mOVAxOTII Tg animals showed normal deletion of transgenic CD4+ T cells despite the presence of anti-CD154 mAb. Conclusions There are differing requirement for CD40-CD154 interaction in negative selection of CD4+ thymocytes.