The organizational integrity of the adaptive immune system is determined by functionally discrete subsets of CD4+ T cells, but it has remained unclear to what extent lineage choice is influenced by clonotypically expressed T-cell receptors (TCRs). To address this issue, we used a high-throughput approach to profile the αβ TCR repertoires of human naive and effector/memory CD4+ T-cell subsets, irrespective of antigen specificity. Highly conserved physicochemical and recombinatorial features were encoded on a subset-specific basis in the effector/memory compartment. Clonal tracking further identified forbidden and permitted transition pathways, mapping effector/memory subsets related by interconversion or ontogeny. Public sequences were largely confined to particular effector/memory subsets, including regulatory T cells (Tregs), which also displayed hardwired repertoire features in the naive compartment. Accordingly, these cumulative repertoire portraits establish a link between clonotype fate decisions in the complex world of CD4+ T cells and the intrinsic properties of somatically rearranged TCRs.

• Klíčová slova
• CDR3 properties, TCR repertoire, helper CD4+ subsets, human, immunology, inflammation, plasticity of CD4+ subsets,
• MeSH
• buněčný rodokmen imunologie   MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• lidé MeSH
• receptory antigenů T-buněk alfa-beta imunologie   MeSH
• T-lymfocyty - podskupiny imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• receptory antigenů T-buněk alfa-beta MeSH

The present study aimed to work out a peptide-based multi-epitope vaccine against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We predicted different B-cell and T-cell epitopes by using the Immune Epitopes Database (IEDB). Homology modeling of the construct was done using SWISS-MODEL and then docked with different toll-like-receptors (TLR4, TLR7, and TLR8) using PatchDock, HADDOCK, and FireDock, respectively. From the overlapped epitopes, we designed five vaccine constructs C1-C5. Based on antigenicity, allergenicity, solubility, different physiochemical properties, and molecular docking scores, we selected the vaccine construct 1 (C1) for further processing. Docking of C1 with TLR4, TLR7, and TLR8 showed striking interactions with global binding energy of -43.48, -65.88, and -60.24 Kcal/mol, respectively. The docked complex was further simulated, which revealed that both molecules remain stable with minimum RMSF. Activation of TLRs induces downstream pathways to produce pro-inflammatory cytokines against viruses and immune system simulation shows enhanced antibody production after the booster dose. In conclusion, C1 was the best vaccine candidate among all designed constructs to elicit an immune response SARS-CoV-2 and combat the coronavirus disease (COVID-19).

• Klíčová slova
• allergenicity, antigenicity, coronavirus, multi-epitopes, pneumonia, vaccine,
• Publikační typ
• časopisecké články MeSH

In mice, the ability of naive T (TN) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8+ TN cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3+ TN cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide-HLA class I Ags. Moreover, CXCR3+ TN cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3+ TN cells were transcriptionally equivalent to murine CXCR3+ TN cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8+ T cells.

• MeSH
• aktivace lymfocytů imunologie   MeSH
• biologické markery MeSH
• buněčná diferenciace imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   metabolismus   MeSH
• dospělí MeSH
• imunofenotypizace MeSH
• imunologická paměť MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• myši MeSH
• receptory CXCR3 metabolismus   MeSH
• senioři MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• biologické markery MeSH
• CXCR3 protein, human MeSH Prohlížeč
• receptory CXCR3 MeSH

The fetus is thought to be protected from exposure to foreign antigens, yet CD45RO+ T cells reside in the fetal intestine. Here we combined functional assays with mass cytometry, single-cell RNA sequencing and high-throughput T cell antigen receptor (TCR) sequencing to characterize the CD4+ T cell compartment in the human fetal intestine. We identified 22 CD4+ T cell clusters, including naive-like, regulatory-like and memory-like subpopulations, which were confirmed and further characterized at the transcriptional level. Memory-like CD4+ T cells had high expression of Ki-67, indicative of cell division, and CD5, a surrogate marker of TCR avidity, and produced the cytokines IFN-γ and IL-2. Pathway analysis revealed a differentiation trajectory associated with cellular activation and proinflammatory effector functions, and TCR repertoire analysis indicated clonal expansions, distinct repertoire characteristics and interconnections between subpopulations of memory-like CD4+ T cells. Imaging mass cytometry indicated that memory-like CD4+ T cells colocalized with antigen-presenting cells. Collectively, these results provide evidence for the generation of memory-like CD4+ T cells in the human fetal intestine that is consistent with exposure to foreign antigens.

• MeSH
• antigen Ki-67 genetika   imunologie   metabolismus   MeSH
• antigen prezentující buňky cytologie   imunologie   metabolismus   MeSH
• antigeny CD5 genetika   imunologie   metabolismus   MeSH
• CD4-pozitivní T-lymfocyty cytologie   imunologie   metabolismus   MeSH
• imunofenotypizace MeSH
• imunologická paměť genetika   imunologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• plod cytologie   imunologie   metabolismus   MeSH
• průtoková cytometrie MeSH
• stanovení celkové genové exprese metody   MeSH
• střeva cytologie   embryologie   imunologie   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• vývojová regulace genové exprese imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen Ki-67 MeSH
• antigeny CD5 MeSH

Age-related changes can significantly alter the state of adaptive immune system and often lead to attenuated response to novel pathogens and vaccination. In present study we employed 5'RACE UMI-based full length and nearly error-free immunoglobulin profiling to compare plasma cell antibody repertoires in young (19-26 years) and middle-age (45-58 years) individuals vaccinated with a live yellow fever vaccine, modeling a newly encountered pathogen. Our analysis has revealed age-related differences in the responding antibody repertoire ranging from distinct IGH CDR3 repertoire properties to differences in somatic hypermutation intensity and efficiency and antibody lineage tree structure. Overall, our findings suggest that younger individuals respond with a more diverse antibody repertoire and employ a more efficient somatic hypermutation process than elder individuals in response to a newly encountered pathogen.

• Klíčová slova
• age, immunoglobulin repertoire, plasma cell, vaccination, yellow fever,
• MeSH
• aktivní imunita * genetika   MeSH
• B-lymfocyty imunologie   metabolismus   MeSH
• dospělí MeSH
• imunoglobuliny - konstantní oblasti genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• protilátky virové imunologie   MeSH
• receptory antigenů B-buněk genetika   metabolismus   MeSH
• somatická hypermutace imunoglobulinových genů MeSH
• těžké řetězce imunoglobulinů genetika   MeSH
• vakcína proti žluté zimnici imunologie   MeSH
• vakcinace MeSH
• žlutá zimnice prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• imunoglobuliny - konstantní oblasti MeSH
• protilátky virové MeSH
• receptory antigenů B-buněk MeSH
• těžké řetězce imunoglobulinů MeSH
• vakcína proti žluté zimnici MeSH