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Thymus-derived glucocorticoids regulate antigen-specific positive selection

M S Vacchio1, J D Ashwell

  • 1Laboratory of Immunology, Division of Hematologic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20852, USA.

The Journal of Experimental Medicine
|June 2, 1997
PubMed
Summary
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Glucocorticoids are crucial for T cell development in the thymus. Inhibiting their production impairs positive selection, indicating a balance between T cell receptor and glucocorticoid signaling is vital for thymocyte survival.

Area of Science:

  • Immunology
  • Cell Biology
  • Developmental Biology

Background:

  • T cell antigen receptor (TCR) avidity for self antigen/MHC is thought to dictate thymocyte fate.
  • The mechanism discriminating positive (survival) vs. negative (death) selection remains unclear.
  • Glucocorticoids produced in the thymus can antagonize TCR-induced deletion.

Purpose of the Study:

  • To investigate the role of glucocorticoids in MHC-dependent thymocyte selection.
  • To understand how glucocorticoids influence the balance between positive and negative selection.

Main Methods:

  • Organ culture of thymocytes from alpha/beta-TCR transgenic mice.
  • Inhibition of corticosteroid biosynthesis during thymocyte development.
  • Analysis of thymocyte survival and apoptosis in response to altered glucocorticoid levels.

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Main Results:

  • Inhibition of glucocorticoid production led to antigen- and MHC-specific loss of thymocytes.
  • Specifically, thymocytes undergoing positive selection were lost.
  • Apoptosis increased in CD4+CD8+ thymocytes with transgenic TCRs recognizing self antigen/MHC.

Conclusions:

  • A balance between T cell receptor (TCR) and glucocorticoid receptor signaling influences thymocyte development.
  • Glucocorticoids permit survival of thymocytes with low-to-moderate avidity for self antigen/MHC.
  • This signaling balance is critical for proper T cell selection in the thymus.