Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease

J Exp Med. 2012 Sep 24;209(10):1781-95. doi: 10.1084/jem.20120058. Epub 2012 Sep 3.

Abstract

Negative selection and regulatory T (T reg) cell development are two thymus-dependent processes necessary for the enforcement of self-tolerance, and both require high-affinity interactions between the T cell receptor (TCR) and self-ligands. However, it remains unclear if they are similarly impacted by alterations in TCR signaling potential. We generated a knock-in allele (6F) of the TCR ζ chain gene encoding a mutant protein lacking signaling capability whose expression is controlled by endogenous ζ regulatory sequences. Although negative selection was defective in 6F/6F mice, leading to the survival of autoreactive T cells, 6F/6F mice did not develop autoimmune disease. We found that 6F/6F mice generated increased numbers of thymus-derived T reg cells. We show that attenuation of TCR signaling potential selectively impacts downstream signaling responses and that this differential effect favors Foxp3 expression and T reg cell lineage commitment. These results identify a potential compensatory pathway for the enforcement of immune tolerance in response to defective negative selection caused by reduced TCR signaling capability.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Alleles
  • Animals
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology*
  • Bone Marrow Transplantation / immunology
  • Clonal Selection, Antigen-Mediated / genetics
  • Clonal Selection, Antigen-Mediated / immunology*
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • Gene Expression
  • Gene Order
  • Homeodomain Proteins / genetics
  • Immunologic Memory
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation
  • Phenotype
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Thymocytes / immunology
  • Thymocytes / metabolism

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Homeodomain Proteins
  • Receptors, Antigen, T-Cell
  • RAG-1 protein