Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness

J Clin Invest. 2012 Jul;122(7):2384-94. doi: 10.1172/JCI63067. Epub 2012 Jun 1.


Generation of a self-tolerant but antigen-responsive T cell repertoire occurs in the thymus. Although glucocorticoids are usually considered immunosuppressive, there is also evidence that they play a positive role in thymocyte selection. To address the question of how endogenous glucocorticoids might influence the adaptive immune response, we generated GRlck-Cre mice, in which the glucocorticoid receptor gene (GR) is deleted in thymocytes prior to selection. These mice were immunocompromised, with reduced polyclonal T cell proliferative responses to alloantigen, defined peptide antigens, and viral infection. This was not due to an intrinsic proliferation defect, because GR-deficient T cells responded normally when the TCR was cross-linked with antibodies or when the T cell repertoire was "fixed" with αβ TCR transgenes. Varying the affinity of self ligands in αβ TCR transgenic mice showed that affinities that would normally lead to thymocyte-positive selection caused negative selection, and alterations in the TCR repertoire of polyclonal T cells were confirmed by analysis of TCR Vβ CDR3 regions. Thus, endogenous glucocorticoids are required for a robust adaptive immune response because of their promotion of the selection of T cells that have sufficient affinity for self, and the absence of thymocyte glucocorticoid signaling results in an immunocompromised state.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity*
  • Animals
  • Antigens, Viral / immunology
  • CD4 Antigens / metabolism
  • CD8 Antigens / metabolism
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Glucocorticoids / physiology*
  • Glycoproteins / immunology
  • Isoantigens / immunology
  • Lymph Nodes / cytology
  • Lymphocyte Count
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Peptide Fragments / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism
  • Signal Transduction
  • Thymocytes / immunology*
  • Thymocytes / metabolism
  • Thymocytes / physiology
  • Thymus Gland / cytology
  • Viral Proteins / immunology


  • Antigens, Viral
  • CD4 Antigens
  • CD8 Antigens
  • Glucocorticoids
  • Glycoproteins
  • Isoantigens
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • Receptors, Glucocorticoid
  • Viral Proteins
  • glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus