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Memory CD8+ T cells mediate early pathogen-specific protection through localized delivery of antigen-dependent chemokines and IFNgamma to clusters of inflammatory monocytes

ABSTRACT: While cognate antigen-driven clonal expansion is a cardinal feature of memory CD8+ T cell effective response, inflammatory cytokines also orchestrates their rapid activation and production of IFNᵧ, contributing to innate mechanisms of protection. Despite antigen-independent secretion, IFNᵧ accounts for a large part of antigen-dependent protection in a multitude of infections, yet how cognate antigen enables memory CD8+ T cell-derived IFNᵧ to achieve host protection remains unknown. Herein, using distinct models of immunization, we establish that cognate antigen (Ag) recognition by memory CD8+ T cells on conventional CD11chi dendritic cells initiates their coordinated production of a burst of chemokines (CCL3, CCL4, XCL1) under the transcriptional control of IRF4. Using intravital microscopy imaging, we further reveal that memory CD8+ T cells undergo Ag-mediated arrest in splenic red pulp clusters of CCR2+ monocytes to deliver them with IFNᵧ- and Ag-dependent chemokine-potentiating microbicidal activities. These results establish that effective memory CD8+ T cell responses require coordinated stepwise processes that quickly restrict pathogen growth and optimize the local delivery of effector molecules before clonal expansion occurs.

ORGANISM(S): Mus musculus

PROVIDER: GSE160280 | GEO | 2020/10/29

REPOSITORIES: GEO

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Project description:Many aged individuals develop monoclonal expansions of CD8 T cells. These expansions are derived from a CD8 memory T cell that outcompetes neighboring CD8 T cells. The molecular alterations within clonal expansions that confer this competitive advantage relative to other CD8 T cells remains unknown. These microarray experiments were designed to identify genes differentially expressed in age-associated expansions of CD8 memory T cells relative to polyclonal CD8 memory T cells found in the same aged mice. Subsequent analysis of these data identified two major types of clonal expansions, distinguished by expression level of integrin a4 mRNA and protein. Based on this classification, Expansion_rep1 belongs to the integrin a4 high subtype of clonal expansions. In contrast, reps 2, 4, and 5 belong to the integrin a4 low subtype of clonal expansions. Given the divergent biological properties of these two subtypes of clonal expansions, we have focused genes differentially expressed between Expansion_rep 2, 4, and 5 and their paired PolyclonalAged samples. Experiment Overall Design: A total of 8 samples were analyzed for gene expression using the Affymetrix mouse genome 430 2.0 microarray platform. The experimental samples of interest were age-associated clonal expansions of CD8 memory T cells. We purified four clonal expansions from four independent, aged mice (indicated as "Expansion" rep1 2, 3, 4). For each clonal expansion of CD8 memory T cells that was purified, there was a paired control in which polyclonal CD8 memory T cells were harvested from the same aged mouse (denoted as "PolyclonalAged" rep1, 2, 3, 4). These paired samples allow one to consider gene expression changes from mice which have undergone the same age-associated changes in biology. The predominant comparison this study focused on was changes in gene expression between age-associated clonal expansions of CD8 memory T cells and their paired, polyclonal CD8 memory T cells. A total of 4 of these pairs were collected.

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Memory CD8+ T cells mediate early pathogen-specific protection through localized delivery of antigen-dependent chemokines and IFNgamma to clusters of inflammatory monocytes

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