Coreceptor Signal Strength Regulates Positive Selection but Does Not Determine CD4/CD8 Lineage Choice in a Physiologic In Vivo Model

• Published in: Journal of Immunology 2006-11, Vol.177 (10), p.6613-6625
• Main Authors: Erman, Batu, Alag, Amala S, Dahle, Oyvind, van Laethem, Francois, Sarafova, Sophia D, Guinter, Terry I, Sharrow, Susan O, Grinberg, Alexander, Love, Paul E, Singer, Alfred
• Format: Article
• Language: English
• Subjects: Animals; CD4 Antigens - biosynthesis; CD4 Antigens - genetics; CD4 Antigens - physiology; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8 Antigens - biosynthesis; CD8 Antigens - genetics; CD8 Antigens - physiology; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Line; Cell Lineage - genetics; Cell Lineage - immunology; Female; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Transgenic; Models, Immunological; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - genetics; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.177.10.6613

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 CD8alpha gene has been re-engineered to encode the stronger signaling cytoplasmic tail of CD4, with the re-engineered CD8alpha 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.