CD28 and ITK signals regulate autoreactive T cell trafficking.

Therapeutic Approaches
Paradigms and Technologies
Methods Development

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

Jain, Nitya; Miu, Bing; Jiang, Jian-Kang; McKinstry, Kai K; Prince, Amanda; Swain, Susan L; Greiner, Dale L; Thomas, Craig; Sanderson, Michael J; Berg, Leslie J; Kang, Joonsoo;

Keywords

  • Animals
  • Antigens, CD28/ physiology
  • CHO Cells
  • CTLA-4 Antigen/ genetics
  • Cells, Cultured
  • Chemotaxis, Leukocyte/ genetics
  • Cricetinae
  • Cricetulus
  • Female
  • Homeostasis/ immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Protein-Tyrosine Kinases/ physiology
  • Signal Transduction/ physiology
  • T-Lymphocytes/ physiology

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