Overtly self-reactive T cells are removed during thymic selection. However, it has been recently established that T cell self-reactivity promotes protective immune responses. Apparently, the level of self-reactivity of mature T cells must be tightly balanced. Our mathematical model and experimental data show that the dynamic regulation of CD4- and CD8-LCK coupling establish the self-reactivity of the peripheral T cell pool. The stoichiometry of the interaction between CD8 and LCK, but not between CD4 and LCK, substantially increases upon T cell maturation. As a result, peripheral CD8+ T cells are more self-reactive than CD4+ T cells. The different levels of self-reactivity of mature CD8+ and CD4+ T cells likely reflect the unique roles of these subsets in immunity. These results indicate that the evolutionary selection pressure tuned the CD4-LCK and CD8-LCK stoichiometries, as they represent the unique parts of the proximal T cell receptor (TCR) signaling pathway, which differ between CD4+ and CD8+ T cells.

Department of Biomedicine University Hospital and University of Basel 4031 Basel Switzerland

Department of Biomedicine University Hospital and University of Basel 4031 Basel Switzerland; Institute for Immunology Biomedical Center Munich Ludwig Maximilians University Munich Germany

Department of Biomedicine University Hospital and University of Basel 4031 Basel Switzerland; Peter Doherty Institute University of Melbourne Melbourne Australia

Division of Animal Physiology and Immunology School of Life Sciences Weihenstephan Technical University of Munich Freising Germany

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences 14220 Prague Czech Republic

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Unique roles of co-receptor-bound LCK in helper and cytotoxic T cells

Self-reactivity of CD8 T-cell clones determines their differentiation status rather than their responsiveness in infections