Peripheral control of autoimmunity (1)

In addition to the central mechanism described in the previous lecture, there are several peripheral control systems for autoreactivity, i.e. within the secondary lymphoid organs and, potentially, the tissues involved in an immune response. The first mechanism involves regulatory T cells, first demonstrated by T cell transfer experiments in mice and neonatal thymectomy. A rare hereditary human pathology (IPEX syndrome) characterized by severe inflammation of the digestive tract with perinatal onset, associated with the onset of several autoimmune (diabetes, anemia, etc.) and allergic diseases, is caused by an abnormality in the differentiation of regulatory T lymphocytes (Treg). This population has now been identified. Its development depends on a transcription factor: FOXP3, which is deficient in IPEX syndrome. These cells are generated like other T lymphocytes in the thymus, but, in the periphery, effector CD4 T lymphocytes can also, under defined environmental conditions, transform into regulatory cells expressing FOXP3. It has been shown that, during intrathymic differentiation, Treg generation is proportional to the affinity of the T receptor for the self antigen. Thus, in an operationally logical way, the presence of self antigens preferentially activates regulatory rather than effector cells. These Tregs are themselves subject to homeostatic control, enabling an appropriate balance to be struck between the necessary effector response to foreign antigens (infections) and the control of autoimmunity. This balance is partly achieved by the consumption of Tregs by interleukin 2 (IL2), as they recirculate in the thymus. IL2 is an essential cytokine for Treg differentiation, survival and expansion. Thus, thymic IL2 levels have been shown to control Treg development. In addition, recent results obtained using fine cell imaging techniques (histocytometry) in vivo indicate that Tregs are strategically placed in secondary lymphoid organs, i.e. in contact with antigen-presenting dendritic cells at the entrance to lymph nodes. They can thus be locally activated and exert in situ their regulatory functions on effector cells via membrane molecules (CTLA4, etc.) and the secretion of inhibitory cytokines (IL10, TGFb). Tregs are also present in large numbers in the intestine (colon), where they control the immune response to physiological intestinal flora and prevent excessive inflammation. The molecules involved in these processes have been partially identified.