Potential roles of self-reactive T cells in autoimmunity: lessons from cancer immunology

The immune system is a complex arrangement of cells and molecules that preserve the integrity of the organism by eliminating all elements judged to be dangerous. Several regulatory mechanisms function to terminate immune responses to antigens, return the immune system to a basal state after the antigen has been cleared, and maintain unresponsiveness, or tolerance, to self-antigens. In recent years, reports have described T cell responses to several proteins involved in regulating the immune system, particularly under malignant conditions. The present review highlights specific T cells that recognize proteins involved in three, well-defined immunosuppressive mechanisms: (1) inhibitory T cell pathways (i.e., PD-L1), (2) regulatory T cells (i.e., Foxp3(+)), and (3) metabolic enzymes, like indoleamine-2,3-dioxygenase. Cytotoxic T cells can eliminate regulatory cells, thereby suppressing and/or delaying local immune suppression; conversely, regulatory CD4(+) and non-cytotoxic CD8(+) T cells enhance target-mediated immune suppression. The apparent lack of tolerance against endogenous proteins expressed by regulatory cells is intriguing, because it suggests that self-reactive T cells play a general role of fine-tuning the immune system. Thus, T cell responses may be generally used to maintain the homeostasis of the immune system. Further exploration is warranted to investigate the potential role of auto-reactive T cells under different physiological and/or pathological conditions.