CD8 is down(regulated) for tolerance.

CD8 downregulation is an overlooked component of self-reactive CD8+ T cell tolerance. CD8 downregulation is accompanied by T cell inhibition at the signaling and transcriptional levels. Loss of CD8 expression impairs the capacity of T cells to engage peptide-major histocompatibility complex complexes. CD8 downregulation may be a temporary event, as cells may regain CD8 expression and effector function. CD8 downregulation in mammals may be a part of a multilayered mechanism that inactivates self-reactive CD8+ T cells. Loss of CD8 may impair their capacity to engage target cells, while other simultaneous changes curb their activation and effector functions. Understanding this process represents a central element in our interpretation of CD8+ T cell physiology and its role in autoimmune diseases and cancer immunology. Activated CD8+ T cells directly kill target cells. Therefore, the regulation of their function is central to avoiding immunopathology. Mechanisms that curb effector functions in CD4+ and CD8+ T cells are mostly shared, yet important differences occur. Here, we focus on the control of CD8+ T cell activity and discuss the importance of a poorly understood aspect of tolerance that directly impairs engagement of target cells: the downregulation of CD8. We contextualize this process and propose that it represents a key element during CD8+ T cell modulation. [ABSTRACT FROM AUTHOR]