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Regulated Costimulation in the Thymus Is Critical for T Cell Development: Dysregulated CD28 Costimulation Can Bypass the Pre-TCR Checkpoint

Joy A. Williams^*, Karen S. Hathcock^*, David Klug^*, Yohsuke Harada, Baishakhi Choudhury^*, James P. Allison, Ryo Abe and Richard J. Hodes^1,*,

^* Experimental Immunology Branch, National Cancer Institute, and National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; Research Institute for Biological Sciences, Science University of Tokyo, Chiba, Japan; and University of California, Berkeley, CA 94720

Expression of CD28 is highly regulated during thymic development, with CD28 levels extremely low on immature thymocytes but increasing dramatically as CD4^–CD8^– cells initiate expression of TCR. B7-1 and B7-2, the ligands for CD28, have a restricted distribution in the thymic cortex where immature thymocytes reside and are more highly expressed in the medulla where the most mature thymocytes are located. To determine the importance of this regulated CD28/B7 expression for T cell development, we examined the effect of induced CD28 signaling of immature thymocytes in CD28/B7-2 double-transgenic mice. Strikingly, we found that differentiation to the CD4⁺CD8⁺ stage in CD28/B7-2 transgenics proceeds independent of the requirement for TCR expression manifest in wild-type thymocytes, occurring even in Rag^– or CD3^– knockouts. These findings indicate that signaling of immature thymocytes through CD28 in the absence of TCR- or pre-TCR-derived signals can promote an aberrant pathway of T cell differentiation and highlight the importance of finely regulated physiologic expression of CD28 and B7 in maintaining integrity of the "" checkpoint for pre-TCR/TCR-dependent thymic differentiation.

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