A Broad Range of Self-Reactivity Drives Thymic Regulatory T Cell Selection to Limit Responses to Self

Immunity. 2012 Sep 21;37(3):475-86. doi: 10.1016/j.immuni.2012.07.009. Epub 2012 Aug 23.

Abstract

The degree of T cell self-reactivity considered dangerous by the immune system, thereby requiring thymic selection processes to prevent autoimmunity, is unknown. Here, we analyzed a panel of T cell receptors (TCRs) with a broad range of reactivity to ovalbumin (OVA(323-339)) in the rat insulin promoter (RIP)-mOVA self-antigen model for their ability to trigger thymic self-tolerance mechanisms. Thymic regulatory T (Treg) cell generation in vivo was directly correlated with in vitro TCR reactivity to OVA-peptide in a broad ~1,000-fold range. Interestingly, higher TCR affinity was associated with a larger Treg cell developmental "niche" size, even though the amount of antigen should remain constant. The TCR-reactivity threshold to elicit thymic negative selection and peripheral T cell responses was ~100-fold higher than that of Treg cell differentiation. Thus, these data suggest that the broad range of self-reactivity that elicits thymic Treg cell generation is tuned to secure peripheral tolerance to self.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autoantigens / immunology*
  • Cell Differentiation / immunology
  • Female
  • Flow Cytometry
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Transgenic
  • Ovalbumin / chemistry
  • Ovalbumin / immunology
  • Peptides / immunology
  • Peripheral Tolerance / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Self Tolerance / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Thymus Gland / immunology
  • Thymus Gland / metabolism

Substances

  • Autoantigens
  • Peptides
  • Receptors, Antigen, T-Cell
  • Ovalbumin