Autoimmune effector memory T cells: the bad and the good

Abstract

Immunological memory is a hallmark of adaptive immunity, a defense mechanism endowed to vertebrates during evolution. However, an autoimmune pathogenic role of memory lymphocytes is also emerging with accumulating evidence, despite reasonable skepticism on their existence in a chronic setting of autoimmune damage. It is conceivable that autoimmune memory would be particularly harmful since memory cells would constantly "remember" and attack the body's healthy tissues. It is even more detrimental given the resistance of memory T cells to immunomodulatory therapies. In this review, we focus on self-antigen-reactive CD(+) effector memory T (TEM) cells, surveying the evidence for the role of the T(EM) compartment in autoimmune pathogenesis. We will also discuss the role of T(EM) cells in chronic and acute infectious disease settings and how they compare to their counterparts in autoimmune diseases. With their long-lasting potency, the autoimmune T(EM) cells could also play a critical role in anti-tumor immunity, which may be largely based on their reactivity to self-antigens. Therefore, although autoimmune T(EM) cells are "bad" due to their role in relentless perpetration of tissue damage in autoimmune disease settings, they are unlikely a by-product of industrial development along the modern surge of autoimmune disease prevalence. Rather, they may be a product of evolution for their "good" in clearing damaged host cells in chronic infections and malignant cells in cancer settings.

Fig. 1

Predominant subsets of memory T cells in infections, tumors and autoimmune diseases. (1) Persistence of antigens in chronic infections, tumor microenvironment and autoimmune disease settings leads to the increased formation of the effector memory T (T_EM) cell subset. (2) T_EM cells are exhausted in settings of chronic infections and tumors. (3) In autoimmune diseases, T_EM cells are not exhausted, making them highly pathogenic. Their longevity and active functionality perpetuate autoimmune damage. (4) Persistence of antigens in chronic infections, tumors and autoimmune disease settings diminishes the formation of the central memory T (T_CM) cells and possibly the tissue-resident memory T (T_RM) cell subsets. (5) Immune control genes such as CTLA4 are highly polymorphic, and the polymorphisms that may promote T_EM cells are well preserved in human populations despite their deleterious potential in causing autoimmune diseases. These genetic variations suggest that the differentiation of autoimmune T_EM cells may have evolved for their beneficial potential in clearing unhealthy cells in chronic infections or boosting anti-tumor immunity. Further studies are needed to bridge the genetic discoveries to immunobiology and pathophysiology