Quantitative impact of thymic selection on Foxp3+ and Foxp3– subsets of self-peptide/MHC class II-specific CD4+ T cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-08, Vol.108 (35), p.14602-14607
• Main Authors: Moon, James J, Dash, Pradyot, Oguin, Thomas H. III, McClaren, Jennifer L, Chu, H. Hamlet, Thomas, Paul G, Jenkins, Marc K
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Autoantigens; Autoantigens - immunology; Autoimmunity; Avidity; Biological Sciences; CD4 antigen; CD4-positive T-lymphocytes; CD4-Positive T-Lymphocytes - immunology; Clonal Deletion; Forkhead Transcription Factors - analysis; Foxp3 protein; Genotype & phenotype; Histocompatibility Antigens Class II - immunology; Immune Tolerance; Immunity; Immunoregulation; Ligands; Lymph nodes; Lymphocytes T; Major histocompatibility complex; Mice; Peptides; Receptors; Receptors, Antigen, T-Cell - physiology; Rodents; T cell antigen receptors; T cell receptors; T lymphocytes; T-cell receptor; T-Lymphocytes, Regulatory - immunology; Thymus; Thymus Gland - immunology; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1109806108

It is currently thought that T cells with specificity for self-peptide/MHC (pMHC) ligands are deleted during thymic development, thereby preventing autoimmunity. In the case of CD4+ T cells, what is unclear is the extent to which self-peptide/MHC class II (pMHCII)-specific T cells are deleted or become Foxp3+ regulatory T cells. We addressed this issue by characterizing a natural polyclonal pMHCII-specific CD4+ T-cell population in mice that either lacked or expressed the relevant antigen in a ubiquitous pattern. Mice expressing the antigen contained one-third the number of pMHCII-specific T cells as mice lacking the antigen, and the remaining cells exhibited low TCR avidity. In mice lacking the antigen, the pMHCII-specific T-cell population was dominated by phenotypically naive Foxp3– cells, but also contained a subset of Foxp3+ regulatory cells. Both Foxp3– and Foxp3+ pMHCII-specific T-cell numbers were reduced in mice expressing the antigen, but the Foxp3+ subset was more resistant to changes in number and TCR repertoire. Therefore, thymic selection of self-pMHCII–specific CD4+ T cells results in incomplete deletion within the normal polyclonal repertoire, especially among regulatory T cells.