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The roles of c‐rel and interleukin‐2 in tolerance: a molecular explanation of self–nonself discrimination
Author(s) -
Liou HsiouChi,
Smith Kendall A
Publication year - 2011
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2010.120
Subject(s) - biology , immunology , autoimmunity , immunity , clonal deletion , t lymphocyte , immune tolerance , microbiology and biotechnology , antigen , immune system , t cell , t cell receptor
The molecular mechanisms responsible for the exquisite discrimination between self and nonself molecules have remained enigmatic despite intense investigation. However, with the availability of adequate amounts of anergic lymphocytes produced by double transgenic mice, large numbers of immature B cells from sublethaly irradiated, hematopoietically‐synchronized mice, as well as critical gene‐deleted mice, it has been possible for the first time to uncover plausible molecular mechanisms that lead to tolerance versus immunity. The Rel family of transcription factors is expressed at different stages of lymphocyte maturation and differentiation. C‐Rel is not activated by immature lymphocytes, which undergo either anergy or apoptosis when triggered by antigen receptors, but c‐Rel is activated in mature lymphocytes. Antigen receptor triggering induces c‐Rel‐dependent survival and proliferative genetic programs. In T cells, a critical c‐Rel‐dependent gene encodes the T‐cell growth factor interleukin‐2 (IL‐2). Thus, T cells from c‐Rel gene‐deleted mice produce inadequate quantities of IL‐2, which renders them immunocompromised and unable to mount normal T‐cell proliferative and differentiative responses. In the face of absolute IL‐2 deficiency from birth, severe, multiorgan autoimmunity gradually ensues. Also, with more subtle IL‐2 deficiency, organ/tissue‐specific autoimmune disease becomes evident. Accordingly, both c‐Rel and IL‐2 appear to be key molecules for tolerance versus immunity, and doubtless will become foci for continued investigation, as well as future therapeutic targets in autoimmune diseases.