CD28 and ITK signals regulate autoreactive T cell trafficking
Department of Pathology; Program in Molecular Medicine; Department of Microbiology and Physiological Systems
Animals; Antigens, CD28; CHO Cells; CTLA-4 Antigen; Cells, Cultured; Chemotaxis, Leukocyte; Cricetinae; Cricetulus; Female; Homeostasis; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Protein-Tyrosine Kinases; Signal Transduction; T-Lymphocytes
Immunology of Infectious Disease | Immunopathology
Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.
DOI of Published Version
Nat Med. 2013 Dec;19(12):1632-7. doi: 10.1038/nm.3393. Epub 2013 Nov 24. Link to article on publisher's site
Jain, Nitya; Miu, Bing; Jiang, Jian-kang; McKinstry, Kai K.; Prince, Amanda L.; Swain, Susan L.; Greiner, Dale L.; Thomas, Craig J.; Sanderson, Michael J.; Berg, Leslie J.; and Kang, Joonso, "CD28 and ITK signals regulate autoreactive T cell trafficking" (2013). University of Massachusetts Medical School Faculty Publications. 804.