T cells are pivotal in the adaptive immune defense, necessitating a delicate balance between robust response against infections and self-tolerance. Their activation involves intricate cross-talk among signaling pathways triggered by the T-cell antigen receptors (TCR) and co-stimulatory or inhibitory receptors. The molecular regulation of these complex signaling networks is still incompletely understood. Here, we identify the adaptor protein ABIN1 as a component of the signaling complexes of GITR and OX40 co-stimulation receptors. T cells lacking ABIN1 are hyper-responsive ex vivo, exhibit enhanced responses to cognate infections, and superior ability to induce experimental autoimmune diabetes in mice. ABIN1 negatively regulates p38 kinase activation and late NF-κB target genes. P38 is at least partially responsible for the upregulation of the key effector proteins IFNG and GZMB in ABIN1-deficient T cells after TCR stimulation. Our findings reveal the intricate role of ABIN1 in T-cell regulation.

• Klíčová slova
• ABIN1, Antigen Receptor, Co-stimulation, T Cells, p38,
• MeSH
• adaptorové proteiny signální transdukční * metabolismus   genetika   MeSH
• aktivace lymfocytů imunologie   genetika   MeSH
• cytotoxické T-lymfocyty * imunologie   metabolismus   MeSH
• diabetes mellitus 1. typu imunologie   genetika   metabolismus   MeSH
• glukokortikoidy indukovaný protein související s TNRF MeSH
• interferon gama metabolismus   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• NF-kappa B metabolismus   MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• receptory OX40 metabolismus   genetika   MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční * MeSH
• glukokortikoidy indukovaný protein související s TNRF MeSH
• interferon gama MeSH
• mitogenem aktivované proteinkinasy p38 MeSH
• NF-kappa B MeSH
• receptory antigenů T-buněk MeSH
• receptory OX40 MeSH
• Tnfrsf18 protein, mouse MeSH Prohlížeč

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

The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated self-antigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14+Sirpα+ population of monocyte-derived dendritic cells (CD14+moDC) that are enriched in the thymic medulla and effectively acquire mTEC-derived antigens in response to the above chemokines. Consistently, the cellularity of CD14+moDC is diminished in mice with MyD88-deficient TECs, in which the frequency and functionality of thymic CD25+Foxp3+ Tregs are decreased, leading to aggravated mouse experimental colitis. Thus, our findings describe a TLR-dependent function of mTECs for the recruitment of CD14+moDC, the generation of Tregs, and thereby the establishment of central tolerance.

• MeSH
• analýza jednotlivých buněk MeSH
• autoantigeny imunologie   MeSH
• autotolerance MeSH
• chemokiny imunologie   metabolismus   MeSH
• dendritické buňky imunologie   MeSH
• epitelové buňky imunologie   metabolismus   MeSH
• kolitida imunologie   MeSH
• lipopolysacharidové receptory metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• převzatá imunita MeSH
• prezentace antigenu MeSH
• průtoková cytometrie MeSH
• receptory imunologické metabolismus   MeSH
• regulační T-lymfocyty imunologie   transplantace   MeSH
• sekvenční analýza RNA MeSH
• separace buněk MeSH
• signální transdukce imunologie   MeSH
• thymus cytologie   imunologie   MeSH
• toll-like receptory metabolismus   MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• autoantigeny MeSH
• Cd14 protein, mouse MeSH Prohlížeč
• chemokiny MeSH
• lipopolysacharidové receptory MeSH
• receptory imunologické MeSH
• Sirpa protein, mouse MeSH Prohlížeč
• toll-like receptory 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