Theoretical Studies of Self-Tolerance: Regulatory T Cells and Anergy

Adaptive immunity of vertebrates is performed by a large repertoire of T and B lymphocytes, characterized by a diversity of receptors in order to recognize a variety of pathogens. The diversity of receptors is generated by somatic recombination during lymphocyte development. Random somatic recombination inevitably produce lymphocytes that recognize proteins constituting a body (self-antigens). If these self-reactive lymphocytes become active in a body, they may cause autoimmunity, immune system attacks a body itself. To avoid this, negative selection remove large number of self-reactive T lymphocytes, but it is unlikely to be complete. In fact, it is suspected that self-reactive T cells are commonly present in the peripheral T cell repertoire. Therefore there must be additional mechanisms to maintain self-tolerance in the periphery. In this talk, I focuses on two mechanisms important for self-tolerance: regulatory T cells and anergy. Regulatory T cell is a subclass of CD4+ T lymphocytes which plays an important role in the prevention of autoimmunity by suppressing other T cells. T cell anergy is defined as a state of unresponsiveness in T cells associated with nonproliferation and a lack of cytokine production. T cells are functionally inactivated following an antigen encounter, but remains alive for extended period of time. I discuss the adaptive significance of these two mechanisms for self-tolerance by defining "fitness" explicitly. The fitness includes the benefit of eliminating pathogens by activating pathogen specific effector T cells, and the harm of activating self-reactive T cells. We can compare the case with a tolerance mechanism and the case without it. Thus the model addresses the question of why a particular mechanism is adopted by the organisms rather than alternatives. The condition in which these tolerance mechanisms are beneficial also help us understand the condition in the body or which properties are regarded as important by the immune system.