Authors
Jain, NityaMiu, 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.
Kang, Joonso
UMass Chan Affiliations
Department of Microbiology and Physiological SystemsProgram in Molecular Medicine
Department of Pathology
Document Type
Journal ArticlePublication Date
2013-12-01Keywords
AnimalsAntigens, 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
Metadata
Show full item recordAbstract
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.Source
Nat Med. 2013 Dec;19(12):1632-7. doi: 10.1038/nm.3393. Epub 2013 Nov 24. Link to article on publisher's siteDOI
10.1038/nm.3393Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30528PubMed ID
24270545Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/nm.3393