ABSTRACT
T cells dynamically interact with multiple, distinct cellular subsets to determine effector and memory differentiation. Here, we developed a platform to quantify cell location in three dimensions to determine the spatial requirements that direct T cell fate. After viral infection, we demonstrated that CD8+ effector T cell differentiation is associated with positioning at the lymph node periphery. This was instructed by CXCR3 signaling since, in its absence, T cells are confined to the lymph node center and alternatively differentiate into stem-like memory cell precursors. By mapping the cellular sources of CXCR3 ligands, we demonstrated that CXCL9 and CXCL10 are expressed by spatially distinct dendritic and stromal cell subsets. Unlike effector cells, retention of stem-like memory precursors in the paracortex is associated with CCR7 expression. Finally, we demonstrated that T cell location can be tuned, through deficiency in CXCL10 or type I interferon signaling, to promote effector or stem-like memory fates.
Subject(s)
Arenaviridae Infections/metabolism , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation , Chemokine CXCL10/metabolism , Chemokine CXCL9/metabolism , Immunologic Memory , Lymph Nodes/metabolism , Precursor Cells, T-Lymphoid/metabolism , Receptors, CXCR3/metabolism , Animals , Arenaviridae Infections/genetics , Arenaviridae Infections/immunology , Arenaviridae Infections/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Cell Lineage , Cells, Cultured , Chemokine CXCL10/genetics , Chemokine CXCL9/genetics , Chemotaxis, Leukocyte , Dendritic Cells/immunology , Dendritic Cells/metabolism , Disease Models, Animal , Host-Pathogen Interactions , Interferon Type I/metabolism , Ligands , Lymph Nodes/immunology , Lymph Nodes/virology , Lymphocytic choriomeningitis virus/immunology , Lymphocytic choriomeningitis virus/pathogenicity , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Precursor Cells, T-Lymphoid/immunology , Precursor Cells, T-Lymphoid/virology , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , Receptors, CCR7/metabolism , Receptors, CXCR3/genetics , Signal Transduction , Stem Cell Niche , Stromal Cells/immunology , Stromal Cells/metabolismABSTRACT
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.
Subject(s)
Epigenesis, Genetic , Interferon Type I , Lymphocytic Choriomeningitis , Lymphocytic choriomeningitis virus , Memory B Cells , Animals , Interferon Type I/metabolism , Interferon Type I/immunology , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/virology , Mice , Lymphocytic choriomeningitis virus/immunology , Memory B Cells/immunology , Mice, Inbred C57BL , Receptor, Interferon alpha-beta/genetics , Immunologic Memory/immunology , Chronic Disease , B-Lymphocyte Subsets/immunology , Single-Cell AnalysisABSTRACT
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.
ABSTRACT
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.