Revisiting Thymic Positive Selection and the Mature T Cell Repertoire for Antigen

To support effective host defense, the T cell repertoire must balance breadth of recognition with sensitivity for antigen. The concept that T lymphocytes are positively selected in the thymus is well established, but how this selection achieves such a repertoire has not been resolved. Here we suggest that it is direct linkage between self and foreign antigen recognition that produces the necessary blend of TCR diversity and specificity in the mature peripheral repertoire, enabling responses to a broad universe of unpredictable antigens while maintaining an adequate number of highly sensitive T cells in a population of limited size. Our analysis also helps to explain how diversity and frequency of antigen-reactive cells in a T cell repertoire are adjusted in animals of vastly different size scale to enable effective antipathogen responses and suggests a possible binary architecture in the TCR repertoire that is divided between germline-related optimal binding and diverse recognition. The T lymphocyte repertoire must balance ligand breadth with response sensitivity. Germain and colleagues discuss how thymic selection on self-peptide-MHC might use germline and diversified receptor sequences to generate an optimal balance of T cell receptor diversity and specificity in the mature peripheral repertoire.