Deletion of CD4 and CD8 coreceptors permits generation of alphabetaT cells that recognize antigens independently of the MHC.
The thymus generates major histocompatibility complex (MHC)-restricted alphabetaT cells that only recognize antigenic ligands in association with MHC or MHC-like molecules. We hypothesized that MHC specificity might be imposed on a broader alphabetaTCR repertoire during thymic selection by CD4 and CD8 coreceptors that bind and effectively sequester the tyrosine kinase Lck, thereby preventing T cell receptor (TCR) signaling by non-MHC ligands that do not engage either coreceptor. This hypothesis predicts that, in coreceptor-deficient mice, alphabeta thymocytes would be signaled by non-MHC ligands to differentiate into alphabetaT cells lacking MHC specificity. We now report that MHC-independent alphabetaT cells were indeed generated in mice deficient in both coreceptors as well as MHC ("quad-deficient" mice) and that such mice contained a diverse alphabetaT cell repertoire whose MHC independence was confirmed at the clonal level. We conclude that CD4 and CD8 coreceptors impose MHC specificity on a broader alphabetaTCR repertoire during thymic selection by preventing thymocytes from being signaled by non-MHC ligands.
Van Laethem
François
F
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sarafova
Sophia D
SD
Park
Jung-Hyun
JH
Tai
Xuguang
X
Pobezinsky
Leonid
L
Guinter
Terry I
TI
Adoro
Stanley
S
Adams
Anthony
A
Sharrow
Susan O
SO
Feigenbaum
Lionel
L
Singer
Alfred
A
D000818:Animals; D015152:Blotting, Northern; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology
D015704:CD4 Antigens; D016827:CD8 Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)