AI Article Synopsis
- Activation of self-reactive T cells and their movement to target tissues causes damage in autoimmune diseases, as seen in mice without CTLA-4.
- The CD28 co-stimulatory pathway is crucial for directing self-reactive T cells to tissues, while the absence of ITK leads to these cells gathering in lymphoid organs instead.
- Inhibitors of ITK can prevent harmful T cell infiltration in autoimmune conditions, suggesting a promising treatment approach for human diseases like type 1 diabetes.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005518 | PMC |
| http://dx.doi.org/10.1038/nm.3393 | DOI Listing |
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