title: CD28 and ITK signals regulate autoreactive T cell trafficking.
abstract: 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.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Nitya
authors.initials: N
authors.lastname: Jain
authors.forename: Bing
authors.initials: B
authors.lastname: Miu
authors.forename: Jian-kang
authors.initials: JK
authors.lastname: Jiang
authors.forename: Kai K
authors.initials: KK
authors.lastname: McKinstry
authors.forename: Amanda
authors.initials: A
authors.lastname: Prince
authors.forename: Susan L
authors.initials: SL
authors.lastname: Swain
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sanderson
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Berg
authors.forename: Joonsoo
authors.initials: J
authors.lastname: Kang
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000502:physiology*; D016466:CHO Cells; D060908:CTLA-4 Antigen / Q000235:genetics; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000235:genetics*; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006706:Homeostasis / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase