Dynamics of the Coreceptor-LCK Interactions during T Cell Development Shape the Self-Reactivity of Peripheral CD4 and CD8 T Cells

Summary 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.
Graphical Abstract
Highlights • Coupling of CD8-LCK but not CD4-LCK increases upon T cell maturation • Dynamics of coreceptor-LCK coupling stoichiometry establish T cell self-reactivity • CD8+ T cells are more self-reactive than CD4+ T cells
Horkova et al. reveal dynamic regulation of the coreceptor-LCK interaction during T cell development, establishing the self-reactivity of mature T cells. Differences between CD8 and CD4 coreceptors cause peripheral CD8+ T cells to be more self-reactive than CD4+ T cells.