Thymocyte autoreactivity and altered thymic epithelial development in the absence of CD28-CD80/86 and CD40-CD40L interactions (36.69)

Abstract

Abstract CD28-CD80/86 and CD40-CD40L interactions are critical to the activation of mature T cells and also have significant effects on T cell development and repertoire selection. Notably, the effects of these costimulatory interactions can be bi-directional, affecting both CD28- and CD40L-expressing T cells and the B7- and CD40-expressing cells with which these T cells interact. We have therefore analyzed development of a self-tolerant T cell repertoire as well as the development of thymic cortico-medullary structure in mice deficient for both the CD28-CD80/86 and CD40-CD40L costimulatory pathways. We find that CD4 thymocytes from CD40/CD80/CD86 KO mice respond vigorously to syngeneic antigen presenting cells, in contrast to the weak responses of thymocytes from either CD40 KO or CD80/CD86 KOs. Interestingly, we also find that the thymic medullary epithelial compartment (mTEC) is uniquely disrupted in CD40/CD80/CD86 deficient mice. The profound reduction in thymic medullary epithelial cells in CD40/CD80/CD86 deficient mice is accompanied by a significant decrease in CD4 SP thymocyte expression of several TNF family members including LTa, LTb, and CD30L. Expression of RANK-L, previously shown to be critical for development of mTEC in the embryonic and adult thymus, is unaffected in CD40/CD80/CD86 deficient thymocytes. These results indicate that thymocyte-mTEC crosstalk mediated either directly or indirectly through CD40 and B7 pathways is critical to thymic stromal development.