| First Author | Mittelstadt PR | Year | 2012 |
| Journal | J Clin Invest | Volume | 122 |
| Issue | 7 | Pages | 2384-94 |
| PubMed ID | 22653054 | Mgi Jnum | J:189951 |
| Mgi Id | MGI:5447478 | Doi | 10.1172/JCI63067 |
| Citation | Mittelstadt PR, et al. (2012) Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness. J Clin Invest 122(7):2384-94 |
| abstractText | 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 alphabeta TCR transgenes. Varying the affinity of self ligands in alphabeta 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 Vbeta 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. |
