Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness.
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.
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
Paul R
PR
Mittelstadt
João P
JP
Monteiro
Jonathan D
JD
Ashwell
D056704:Adaptive Immunity; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D005938:Glucocorticoids / Q000502:physiology*; D006023:Glycoproteins / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D060168:Thymocytes / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology; D014764:Viral Proteins / Q000276:immunology
D000956:Antigens, Viral; D015704:CD4 Antigens; D016827:CD8 Antigens; D005938:Glucocorticoids; D006023:Glycoproteins; D007519:Isoantigens; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D011965:Receptors, Glucocorticoid; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus