Chapter 7 - Peptide editing and its modulation in CD4+ T cell tolerance to self

Abstract

Autoimmunity is a clinical condition of complex and multifactorial etiology characterized by self-tissue damage. It is widely accepted that genetic and environmental factors are responsible for the dysregulation of the immune effector mechanisms that result in such damaging reactions. In this context, CD4+ T cells are considered key players for disease initiation and/or perpetuation in organ-specific autoimmune disorders, such as type 1 diabetes and multiple sclerosis. T cell function ultimately depends on the interaction between the clonotypic T cell receptor (TCR) and cognate peptide-major histocompatibility complex of class II molecules. The stochastic nature of TCR recombination give rise to self-reactive TCRs, which are usually controlled by tolerance mechanisms. Tolerance-inducing mechanisms, as well as T cell activation in the target organs of autoimmune reactions, are sensitive to the display of antigens by MHCII at the surface of antigen presenting cells. Differences between the peptide repertoires displayed in each of these processes are considered essential to drive CD4+ T cell-mediated autoimmunity. In this context, the non-classical human leukocyte antigen II molecules HLA-DM and HLA-DO play essential roles in selecting the peptides displayed for T cell surveillance throughout these processes. In this chapter, the impact of the ncHLAII molecules for the physiological processes related to self-reactive T cell control and activation are discussed.