Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 25, Pages E2550-E2558Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1408482111
Keywords
Zap70; thymic slice; two photon microscopy
Categories
Funding
- California Institute of Regenerative Medicine Post-Doctoral Training [T1-00007]
- Graduate Student Training [TG2-01164]
- Arthritis Foundation Postdoctoral Fellowship [5476]
- National Institutes of Health Grants [AI091580, RC2AR058947, AI064227]
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Positive selection of CD8 T cells in the thymus is thought to be a multistep process lasting 3-4 d; however, the discrete steps involved are poorly understood. Here, we examine phenotypic changes, calcium signaling, and intrathymic migration in a synchronized cohort of MHC class i-specific thymocytes undergoing positive selection in situ. Transient elevations in intracellular calcium concentration ([Ca2+](i)) and migratory pauses occurred throughout the first 24 h of positive selection, becoming progressively briefer and accompanied by a gradual shift in basal [Ca2+](i) over time. Changes in chemokine-receptor expression and relocalization from the cortex to medulla occurred between 12 and 24 h after the initial encounter with positive-selecting ligands, a time frame at which the majority of thymocytes retain CD4 and CD8 expression and still require T-cell receptor (TCR) signaling to efficiently complete positive selection. Our results identify distinct phases in the positive selection of MHC class I-specific thymocytes that are distinguished by their TCR-signaling pattern and intrathymic location and provide a framework for understanding the multistep process of positive selection in the thymus.
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