Jain, NityaMiu, BingJiang, Jian-kangMcKinstry, Kai K.Prince, Amanda L.Swain, Susan LGreiner, Dale L.Thomas, Craig J.Sanderson, Michael J.Berg, Leslie J.Kang, Joonso2022-08-232022-08-232013-12-012015-11-25Nat Med. 2013 Dec;19(12):1632-7. doi: 10.1038/nm.3393. Epub 2013 Nov 24. <a href="http://dx.doi.org/10.1038/nm.3393">Link to article on publisher's site</a>1078-8956 (Linking)10.1038/nm.339324270545https://hdl.handle.net/20.500.14038/30528Activation 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.en-USAnimalsAntigens, CD28CHO CellsCTLA-4 AntigenCells, CulturedChemotaxis, LeukocyteCricetinaeCricetulusFemaleHomeostasisMaleMiceMice, Inbred C57BLMice, Inbred NODMice, KnockoutMice, SCIDProtein-Tyrosine KinasesSignal TransductionT-LymphocytesImmunology of Infectious DiseaseImmunopathologyJournal Articlehttps://escholarship.umassmed.edu/faculty_pubs/8047880379faculty_pubs/804