The kinase LCK and CD4/CD8 co-receptors are crucial components of the T cell antigen receptor (TCR) signaling machinery, leading to key T cell fate decisions. Despite decades of research, the roles of CD4-LCK and CD8-LCK interactions in TCR triggering in vivo remain unknown. In this study, we created animal models expressing endogenous levels of modified LCK to resolve whether and how co-receptor-bound LCK drives TCR signaling. We demonstrated that the role of LCK depends on the co-receptor to which it is bound. The CD8-bound LCK is largely dispensable for antiviral and antitumor activity of cytotoxic T cells in mice; however, it facilitates CD8+ T cell responses to suboptimal antigens in a kinase-dependent manner. By contrast, the CD4-bound LCK is required for efficient development and function of helper T cells via a kinase-independent stabilization of surface CD4. Overall, our findings reveal the role of co-receptor-bound LCK in T cell biology, show that CD4- and CD8-bound LCK drive T cell development and effector immune responses using qualitatively different mechanisms and identify the co-receptor-LCK interactions as promising targets for immunomodulation.

• MeSH
• antigeny CD4 MeSH
• antigeny CD8 metabolismus   MeSH
• cytotoxické T-lymfocyty * metabolismus   MeSH
• myši MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• signální transdukce MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antigeny CD4 MeSH
• antigeny CD8 MeSH
• receptory antigenů T-buněk MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty * MeSH

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.

• Klíčová slova
• CD4, CD8, LCK, T cell, TCR, evolution of the immune system, lymphocyte, self-reactivity, signaling, thymus,
• MeSH
• antigeny metabolismus   MeSH
• buněčná diferenciace MeSH
• CD4-pozitivní T-lymfocyty cytologie   metabolismus   MeSH
• CD8-pozitivní T-lymfocyty cytologie   metabolismus   MeSH
• homeostáza MeSH
• myši inbrední C57BL MeSH
• signální transdukce MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty MeSH