Cell types important for fostering normal thymic medullary epithelial cell development

Tolerance in developing T cells is dependent on medullary thymic epithelial cells (mTEC) and mTEC development in turns requires signals from mature SP thymocytes. Several TNF family receptor-ligand pairs have been shown to be important players in the thymic crosstalk required to foster mTEC development including RANK-RANKL, LTαβ-LTβR and CD40L-CD40. In addition to confirming the important roles of TNF family members in thymic crosstalk, we have recently identified CD28-CD80/86 interactions as an additional pathway important for normal thymic medullary compartment development. CD80 and CD86, similar to LTβR, CD40 and RANK, are expressed by mTEC as well as by bone marrow (BM) derived cells in the thymus. To address the question of which cell type(s) need to express CD80/86, LTβR, CD40 and RANK in order to support mTEC development, we have generated and analyzed BM chimeras or conditional knockout mice in which either non-BM-derived cells (including thymic epithelium) or BM-derived cells express the molecule in question. For LTβR and RANK, we find that expression on radiation-resistant non-BM-derived cells, is required. Interestingly, however, we find that for CD80/86 and CD40, expression on either non-BM-derived or BM-derived cells is sufficient to promote mTEC development. Our findings suggest that models of thymic crosstalk must consider not only communication between TEC and thymocytes but with other bone marrow derived cell types as well.