CD5 instructs extrathymic regulatory T cell development in response to self and tolerizing antigens

Immunity. 2015 Mar 17;42(3):471-83. doi: 10.1016/j.immuni.2015.02.010.


Self-reactive T cells can escape thymic deletion and therefore some of these potentially autoaggressive T cells need to convert into regulatory T (Treg) cells to help control responses against self. However, it remains unknown how peripheral self-reactive T cells are specifically instructed to become Treg cells. We report that CD5, whose expression is upregulated in T cells by self and tolerizing antigens in the thymus and periphery, governed extrathymic Treg cell development. CD5 modified effector cell-differentiating signals that inhibit Treg cell induction. Treg cell conversion of Cd5(-/-) and CD5(lo) T cells was inhibited by even small amounts of interleukin-4 (IL-4), IL-6, and interferon-γ (IFN-γ) produced by bystander lymphocytes, while CD5(hi) T cells resisted this inhibition of Treg cell induction. Our findings further revealed that CD5 promoted Treg cell induction by blocking mechanistic target of rapamycin (mTOR) activation. Therefore CD5 instructs extrathymic Treg cell development in response to self and tolerizing antigens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / genetics
  • Autoantigens / immunology*
  • Bystander Effect / immunology
  • CD5 Antigens / genetics
  • CD5 Antigens / immunology*
  • Cell Differentiation
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Gene Expression Regulation
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interferon-gamma / pharmacology
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology
  • Interleukin-4 / pharmacology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Interleukin-6 / pharmacology
  • Mice
  • Mice, Knockout
  • Peripheral Tolerance
  • Signal Transduction
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / immunology
  • Thymus Gland / cytology
  • Thymus Gland / immunology


  • Autoantigens
  • CD5 Antigens
  • Cd5 protein, mouse
  • Interleukin-6
  • Interleukin-4
  • Interferon-gamma
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse