Manipulating thymic apoptosis for future therapy of autoimmune diseases

In humans, T-cell development takes place in the thymus, which contains an external cortical region and an inner medulla. The skeleton of the thymus consists of stromal cells and is filled with thymocytes in different stages of differentiation. Thymocytes undergo to a development process before becoming mature T lymphocytes ready for export to the peripheral lymphoid organs. Classically, T-cell development has been reported to occur in four steps. First, bone marrow derived thymocytes that express neither CD4 nor CD8 surface antigens (double negative [DN] thymocytes) undergo an extensive phase of proliferation and differentiation and begin to express CD4 and CD8 (step 2: double positive [DP] thymocytes). During a subsequent negative selection process, approximately 5% of these DP cells undergo apoptosis. If these cells are not eliminated, they could differentiate into autoreactive lymphocytes, leading to the development of peripheral autoimmune diseases. In the thymus, a particular population of T regulatory (Treg) cells also develops. These Treg cells migrate to the periphery and are capable of suppressing autoreactive lymphocytes that may have escaped from the negative selection process. Autoimmune diseases are generally the result of insufficient negative selection of autoreactive cells in the thymus or a deficiency in Treg cell production or function. Future therapeutic strategies for autoimmune diseases should exploit manipulations in the negative selection process and/or the differentiation of Treg cells in the thymus.