RESUMO
Antibody-secreting plasma cells (PCs) are generated in secondary lymphoid organs but are reported to reside in an emerging range of anatomical sites. Analysis of the transcriptome of different tissue-resident (Tr)PC populations revealed that they each have their own transcriptional signature indicative of functional adaptation to the host tissue environment. In contrast to expectation, all TrPCs were extremely long-lived, regardless of their organ of residence, with longevity influenced by intrinsic factors like the immunoglobulin isotype. Analysis at single-cell resolution revealed that the bone marrow is unique in housing a compendium of PCs generated all over the body that retain aspects of the transcriptional program indicative of their tissue of origin. This study reveals that extreme longevity is an intrinsic property of TrPCs whose transcriptome is imprinted by signals received both at the site of induction and within the tissue of residence.
Assuntos
Medula Óssea , Plasmócitos , Células da Medula ÓsseaRESUMO
Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions.
Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1 , Linfócitos T Reguladores , Feminino , Masculino , Humanos , Gordura Intra-Abdominal , Citocinas , Inflamação , GlucoseRESUMO
Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet+ subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c+CD80+ cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.
Assuntos
Epigênese Genética , Interferon Tipo I , Coriomeningite Linfocítica , Vírus da Coriomeningite Linfocítica , Células B de Memória , Animais , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Camundongos , Vírus da Coriomeningite Linfocítica/imunologia , Células B de Memória/imunologia , Camundongos Endogâmicos C57BL , Receptor de Interferon alfa e beta/genética , Memória Imunológica/imunologia , Doença Crônica , Subpopulações de Linfócitos B/imunologia , Análise de Célula ÚnicaRESUMO
In this issue of JEM, Lyons-Cohen et al. (https://doi.org/10.1084/jem.20231282) reveal that lymph node macro-clusters provide a spatial niche where CD301b+ cDC2s and CD4+ T cells interact. These integrin-mediated cellular hubs promote enhanced co-stimulation and cytokine signaling to drive Th2 differentiation.
Assuntos
Linfócitos T CD4-Positivos , Integrinas , Diferenciação Celular , LinfonodosRESUMO
TCF-1+ CD8+ T cell populations have emerged as critical determinants for long-lived immunological memory. This cell population has stem-like properties and is implicated in improved disease outcomes by driving sustained killing of infected cells and maintaining the immune-cancer equilibrium. During an immune response, several factors, including antigen deposition and affinity, the inflammatory milieu, and T cell priming dynamics, aggregate to skew CD8+ T cell differentiation. Although these mechanisms are altered between acute and chronic disease settings, phenotypically similar stem-like TCF-1+ CD8+ T cell states are formed in each of these settings. Here, we characterize the specialized microenvironments within lymph nodes and the tumor microenvironment, which foster the generation or re-activation of stem-like TCF-1+ CD8+ T cell populations. We highlight the potential for targeting the stem-like CD8+ T cell niche to enhance vaccination and cancer immunotherapy and to track the trajectory of stem-like CD8+ T cells as biomarkers of therapeutic efficacy.
RESUMO
Developing vaccines that promote CD8 + T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1 + stem cell-like memory T (T SCM ) cells are important determinants of long-lived memory. Yet, the developmental requirements for T SCM formation are unclear. Here, we identify the temporal window for type I interferon (IFN-I) receptor (IFNAR) blockade to drive T SCM cell generation. T SCM cells were transcriptionally distinct and emerged from a transitional precursor of exhausted (T PEX ) cellular state concomitant with viral clearance. T SCM differentiation correlated with T cell retention within the lymph node paracortex, due to increased CXCR3 chemokine abundance which disrupted gradient formation. These affects were due a counterintuitive increase in IFNψ, which controlled cell location. Combining IFNAR inhibition with mRNA-LNP vaccination promoted specific T SCM differentiation and enhanced protection against chronic infection. These finding propose a new approach to vaccine design whereby modulation of inflammation promotes memory formation and function. HIGHLIGHTS: Early, transient inhibition of the type I interferon (IFN) receptor (IFNAR) during acute viral infection promotes stem cell-like memory T (T SCM ) cell differentiation without establishing chronic infection. T SCM and precursor of exhausted (T PEX ) cellular states are distinguished transcriptionally and by cell surface markers. Developmentally, T SCM cell differentiation occurs via a transition from a T PEX state coinciding with viral clearance. Transient IFNAR blockade increases IFNψ production to modulate the ligands of CXCR3 and couple T SCM differentiation to cell retention within the T cell paracortex of the lymph node. Specific promotion of T SCM cell differentiation with nucleoside-modified mRNA-LNP vaccination elicits enhanced protection against chronic viral challenge.