Tuning cross-presentation of apoptotic T cells in immunopathology

Cross-presentation of several long-lived antigens associated with apoptotic T cells requires caspase-dependent cleavage to efficiently deliver antigenic fragments to the processing machinery of antigen-presenting cells. The resulting emergence of a large population of autoreactive CD8(+) T effector cells specific for apoptotic T cell-associated self-epitopes plays a key role in improving immunopathology in several infections and autoimmune diseases. Importantly, they endow mixed polyfunctional type-1, type-2, and type-17 responses and correlate with the chronic progression of various pathological conditions. This evolution is related to the selection of autoreactive CD8(+) T cells with higher T cell receptor avidity, whereas those with lower avidity undergo prompt contraction in patients undergoing disease resolution. The development of mixed responses with divergent differentiation requirements is consistent with distinct sites or kinetics of CD8(+) T cell priming in vivo. Therefore, we propose a strict link among cross-presentation of apoptotic T cells, the generation of high frequencies of mixed autoreactive CD8(+) T cells producing a broad array of cytokines (IFN-γ, IL-17, IL-4, IL-2, etc.), and the progression towards chronic inflammatory diseases.