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.

• 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

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

Linker for activation of T cells (LAT) plays a key role in T-cell antigenic signaling in mammals. Accordingly, LAT orthologues were identified in the majority of vertebrates. However, LAT orthologues were not identified in most birds. In this study, we show that LAT gene is present in genomes of multiple extant birds. It was not properly assembled previously because of its GC-rich content. LAT expression is enriched in lymphoid organs in chicken. The analysis of the coding sequences revealed a strong conservation of key signaling motifs in LAT between chicken and human. Overall, our data indicate that mammalian and avian LAT genes are functional homologues with a common role in T-cell signaling.

• MeSH
• adaptorové proteiny signální transdukční * genetika   MeSH
• fosfoproteiny metabolismus   MeSH
• genom MeSH
• kur domácí genetika   metabolismus   MeSH
• lidé MeSH
• membránové proteiny * genetika   MeSH
• savci genetika   MeSH
• T-lymfocyty metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Regulatory T cells (Tregs) are indispensable for maintaining self-tolerance by suppressing conventional T cells. On the other hand, Tregs promote tumor growth by inhibiting anticancer immunity. In this study, we identified that Tregs increase the quorum of self-reactive CD8+ T cells required for the induction of experimental autoimmune diabetes in mice. Their major suppression mechanism is limiting available IL-2, an essential T-cell cytokine. Specifically, Tregs inhibit the formation of a previously uncharacterized subset of antigen-stimulated KLRK1+ IL-7R+ (KILR) CD8+ effector T cells, which are distinct from conventional effector CD8+ T cells. KILR CD8+ T cells show superior cell-killing abilities in vivo. The administration of agonistic IL-2 immunocomplexes phenocopies the absence of Tregs, i.e., it induces KILR CD8+ T cells, promotes autoimmunity, and enhances antitumor responses in mice. Counterparts of KILR CD8+ T cells were found in the human blood, revealing them as a potential target for immunotherapy.

• MeSH
• CD8-pozitivní T-lymfocyty MeSH
• diabetes mellitus 1. typu * patologie   MeSH
• imunologická tolerance MeSH
• interleukin-2 MeSH
• lektinové receptory NK-buněk - podrodina K MeSH
• lidé MeSH
• myši MeSH
• receptory interleukinu-7 MeSH
• regulační T-lymfocyty * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mature T cells are selected for recognizing self-antigens with low to intermediate affinity in the thymus. Recently, the relative differences in self-reactivity among individual T-cell clones were appreciated as important factors regulating their fate and immune response, but the role of self-reactivity in T-cell biology is incompletely understood. We addressed the role of self-reactivity in T-cell diversity by generating an atlas of mouse peripheral CD8+ T cells, which revealed two unconventional populations of antigen-inexperienced T cells. In the next step, we examined the steady-state phenotype of monoclonal T cells with various levels of self-reactivity. Highly self-reactive clones preferentially differentiate into antigen-inexperienced memory-like cells, but do not form a population expressing type I interferon-induced genes, showing that these two subsets have unrelated origins. The functional comparison of naïve monoclonal CD8+ T cells specific to the identical model antigen did not show any correlation between the level of self-reactivity and the magnitude of the immune response.

• MeSH
• autoantigeny MeSH
• buněčné klony MeSH
• CD8-pozitivní T-lymfocyty * MeSH
• interferon typ I * MeSH
• myši MeSH
• thymus MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

IL-17 mediates immune protection from fungi and bacteria, as well as it promotes autoimmune pathologies. However, the regulation of the signal transduction from the IL-17 receptor (IL-17R) remained elusive. We developed a novel mass spectrometry-based approach to identify components of the IL-17R complex followed by analysis of their roles using reverse genetics. Besides the identification of linear ubiquitin chain assembly complex (LUBAC) as an important signal transducing component of IL-17R, we established that IL-17 signaling is regulated by a robust negative feedback loop mediated by TBK1 and IKKε. These kinases terminate IL-17 signaling by phosphorylating the adaptor ACT1 leading to the release of the essential ubiquitin ligase TRAF6 from the complex. NEMO recruits both kinases to the IL-17R complex, documenting that NEMO has an unprecedented negative function in IL-17 signaling, distinct from its role in NF-κB activation. Our study provides a comprehensive view of the molecular events of the IL-17 signal transduction and its regulation.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• HeLa buňky MeSH
• kinasa I-kappa B genetika   metabolismus   MeSH
• lidé MeSH
• protein-serin-threoninkinasy genetika   metabolismus   MeSH
• receptory interleukinu-17 genetika   metabolismus   MeSH
• signální transdukce * MeSH
• zpětná vazba fyziologická * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH