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-Selection and Positive Selection Checkpoints Are Nonresponsive to IL-7 as Assessed by STAT-5 Phosphorylation1
* Department of Surgery, University of Oklahoma College of Medicine, Tulsa, OK 74135; and
Department of Biochemistry and Microbiology, Oklahoma State University Center for the Health Sciences, Tulsa, OK 74107
Interleukin-7 is widely accepted as a major homeostatic factor involved in T cell development. To assess the IL-7 responsiveness of thymocytes involved in selection processes, we used a new sensitive flow cytometry-based assay to detect intracellular phosphorylation of STAT-5 induced by IL-7 in defined mouse thymocyte subsets. Using this method, we found the earliest thymocyte subset (CD4-CD8-CD25-CD44+) to contain both IL-7-responsive and nonresponsive cells. Transition through the next stages of development (CD4-CD8-CD25+CD44+ and -) was associated with responsiveness of all thymocytes within these populations. Passage of thymocytes through 
-selection resulted in a significant reduction in IL-7 sensitivity. In the next phases of development (TCR- and TCRlowCD69-), thymocytes were completely insensitive to the effects of IL-7. STAT-5 phosphorylation in response to IL-7 was again observed, however, in thymocytes involved in the positive selection process (TCRlowCD69+ and TCRintermediate). As expected, CD4 and CD8 single-positive thymocytes were responsive to IL-7. These findings delineate an IL-7-insensitive population between the -selection and positive selection checkpoints encompassing thymocytes predicted to die by neglect due to failure of positive selection. This pattern of sensitivity suggests a two-signal mechanism by which survival of thymocytes at these checkpoints is governed.
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