Functional heterogeneity of human memory T cell clones primed by pathogens or vaccines
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Mathilde Foglierini
PROVIDER: E-GEOD-64852 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:It is unclear to what extent T helper cells with a different phenotype (chemokine receptor and cytokine production profile) are generated in response to pathogen challenge or vaccination, and whether such heterogeneity can arise among the progeny of a single precursor. We combined cellular methods to isolate antigen specific T cells from different T helper memory subsets of human donors, and next generation sequencing of their TCR. This approach revealed a high level of heterogeneity in the phenotype of human T cells responding to different pathogens/vaccines also at a clonal level, as we could characterize cells bearing an identical T cell receptor with divergent effector properties.
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Project description:The strength of T cell stimulation determines IL-7 responsiveness, recall potential and lineage commitment of primed human CD4+IL-7Rhi T cells; We analyzed how the strength of antigenic stimulation - as determined by dendritic cell (DC) number, DC maturation state and antigen concentration - controls in human CD4+ T cells IL-7R? expression and responsiveness to IL-7, IL-15 and antigen. We found that T cells primed by different strengths of stimulation expressed IL-7R? in different proportions and preferentially on cells that maintained expression of the central memory marker CCR7. However, while CCR7+IL-7Rhi cells generated at high strength of stimulation proliferated vigorously in response to IL-7 or IL-15, CCR7+IL-7Rhi cells generated at low strength of stimulation responded poorly. High cytokine responsiveness was associated with reduced PTEN expression and enhanced s6-kinase activation, consistent with efficient receptor coupling to downstream signalling pathways. Interestingly, while intermediate-stimulated CCR7+IL-7Rhi cells were non-polarized, self-renewed with IL-7 and expanded with antigen, high-stimulated cells generated Th1 effector cells with cytokines but showed impaired IL-2 production and survival with antigen. Gene expression analysis suggested that high-stimulated cells represented pre-Th1 cells with low recall potential and high metabolic state. Taken together these results demonstrate that IL-7 receptor expression and coupling are instructed in T cells by the strength of stimulation and suggest that memory subsets may derive from CCR7+IL-7Rhi precursors that received different strengths of stimulation. Experiment Overall Design: two samples treated with weaker dendritic stimulus, two samples treated with stonger dendritic stimulus.
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Project description:B cells constitute abundant cellular components in inflamed human tissues, but their role in pathogenesis of inflammatory T helper (Th) subsets is still unclear. Here, we demonstrate that B cells, particularly resting naïve B cells, have a previously unrecognized helper function that is involved in shaping the metabolic process and subsequent inflammatory differentiation of T-cell-receptor-primed Th cells. ICOS/ICOSL axis-mediated glucose incorporation and utilization were crucial for inflammatory Th subset induction by B cells, and activation of mTOR was critical for T cell glycolysis in this process. Consistently, upon encountering ICOSL+ B cells, activated effector memory Th cells from patients with rheumatoid arthritis or systemic lupus erythematosus spontaneously differentiated into inflammatory Th subsets. Immunotherapy using an anti-CD20 antibody that specifically depleted B cells in patients with rheumatoid arthritis efficiently abrogated the capabilities of memory Th cells to incorporate and utilize glucose, thereby impairing the pathogenic differentiation of inflammatory Th subsets. To examine the metabolic process of Th cells after interacting with autologous B cells, we applied RNA-sequencing to analyze their transcriptional profiles.
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Project description:T helper cell subsets have unique calcium (Ca2+) signals when activated with identical stimuli. The regulation of these Ca2+ signals and their correlation to the biological function of each T cell subset remains unclear. Trpm4 is a Ca2+-activated cation channel that we found is expressed at higher levels in Th2 cells compared to Th1 cells. Inhibition of Trpm4 expression increased Ca2+ influx and oscillatory levels in Th2 cells and decreased influx and oscillations in Th1 cells. This inhibition of Trpm4 expression also significantly altered T cell cytokine production and motility. Our experiments revealed that decreasing Trpm4 levels divergently regulates nuclear localization of NFAT. Consistent with this, gene profiling did not show Trpm4 dependent transcriptional regulation and T-bet and GATA-3 levels remain identical. Thus, Trpm4 is expressed at different levels on T helper cells and plays a distinctive role in T cell function by differentially regulating Ca2+ signaling and NFAT localization. T helper cell gene expression levels when Trpm4 is inhibited by siRNA or dominant negative Trpm4 construct.
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