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* Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892;
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey; and
Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, MD 20892
TCR signals drive thymocyte development, but it remains controversial what impact, if any, the intensity of those signals have on T cell differentiation in the thymus. In this study, we assess the impact of CD8 coreceptor signal strength on positive selection and CD4/CD8 lineage choice using novel gene knockin mice in which the endogenous CD8
gene has been re-engineered to encode the stronger signaling cytoplasmic tail of CD4, with the re-engineered CD8 gene referred to as CD8.4. We found that stronger signaling CD8.4 coreceptors specifically improved the efficiency of CD8-dependent positive selection and quantitatively increased the number of MHC class I (MHC-I)-specific thymocytes signaled to differentiate into CD8+ T cells, even for thymocytes expressing a single, transgenic TCR. Importantly, however, stronger signaling CD8.4 coreceptors did not alter the CD8 lineage choice of any MHC-I-specific thymocytes, even MHC-I-specific thymocytes expressing the high-affinity F5 transgenic TCR. This study documents in a physiologic in vivo model that coreceptor signal strength alters TCR-signaling thresholds for positive selection and so is a major determinant of the CD4:CD8 ratio, but it does not influence CD4/CD8 lineage choice.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and the Intramural Research Program of the National Institutes of Health, National Institute for Child Health and Human Development.
2 Address correspondence and reprint requests to Dr. Alfred Singer, Experimental Immunology Branch, National Cancer Institute, Building 10 Room 4B36, Bethesda, MD 20892. E-mail address: singera{at}nih.gov
3 Abbreviations used in this paper: MHC-II, MHC class II; MHC-I, MHC class I; DP, double positive; SP, single positive; WT, wild type; TK, thymidine kinase; NEO, neomycin; ES, embryonic stem; LN, lymph node; Tk, T-killer.
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