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 N, Miu B, Jiang J, McKinstry KK, Prince AL, Swain SL, Greiner DL, Thomas CJ, Sanderson MJ, Berg LJ, Kang J. (2013). CD28 and ITK signals regulate autoreactive T cell trafficking. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1038/nm.3393. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/804