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Distinct activation thresholds of human conventional and innate-like memory T cells
Chloe K. Slichter, … , Raphael Gottardo, Martin Prlic
Chloe K. Slichter, … , Raphael Gottardo, Martin Prlic
Published June 2, 2016
Citation Information: JCI Insight. 2016;1(8):e86292. https://doi.org/10.1172/jci.insight.86292.
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Research Article Immunology Inflammation

Distinct activation thresholds of human conventional and innate-like memory T cells

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Abstract

Conventional memory CD8+ T cells and mucosal-associated invariant T cells (MAIT cells) are found in blood, liver, and mucosal tissues and have similar effector potential following activation, specifically expression of IFN-γ and granzyme B. To better understand each subset’s unique contributions to immunity and pathology, we interrogated inflammation- and TCR-driven activation requirements using human memory CD8+ T and MAIT cells isolated from blood and mucosal tissue biopsies in ex vivo functional assays and single cell gene expression experiments. We found that MAIT cells had a robust IFN-γ and granzyme B response to inflammatory signals but limited responsiveness when stimulated directly via their TCR. Importantly, this is not due to an overall hyporesponsiveness to TCR signals. When delivered together, TCR and inflammatory signals synergize to elicit potent effector function in MAIT cells. This unique control of effector function allows MAIT cells to respond to the same TCR signal in a dichotomous and situation-specific manner. We propose that this could serve to prevent responses to antigen in noninflamed healthy mucosal tissue, while maintaining responsiveness and great sensitivity to inflammation-eliciting infections. We discuss the implications of these findings in context of inflammation-inducing damage to tissues such as BM transplant conditioning or HIV infection.

Authors

Chloe K. Slichter, Andrew McDavid, Hannah W. Miller, Greg Finak, Brenda J. Seymour, John P. McNevin, Gabriela Diaz, Julie L. Czartoski, M. Juliana McElrath, Raphael Gottardo, Martin Prlic

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Figure 1

A TCR signal alone is not sufficient for sustained effector function in MAIT cells.

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A TCR signal alone is not sufficient for sustained effector function in ...
(A) A representative flow plot of the CD161hiCCR6hi MAIT cell population in peripheral blood mononuclear cells (PBMC) after gating on CD8+ T cells is shown (left panel). MAIT cell purity was confirmed after sorting CD8+CD161hiCCR6hi cells by determining Vα7.2 expression in a small aliquot (right panel). (B) Five thousand sorted CD8+CD161hiVα7.2+ MAIT cells were rested (no stimulation, black circles); stimulated with anti-CD3/CD28 beads (TCR, red circles) or 100 ng/ml of IL-12/15/18 (blue circles) for 6, 12, or 24 hours; and analyzed for expression of IFN-γ and TNF-α (n = 3). (C) Five thousand sorted CD8+CD45RO+Vα7.2– memory T cells (CD8+ Tmem) were rested (no stimulation, black circles); stimulated with anti-CD3/CD28 beads (TCR, red circles) or 100 ng/ml of IL-12/15/18 (blue circles) for 6, 12, or 24 hours; and analyzed for expression of IFN-γ and TNF-α (n = 3). Data displayed are the average of 2–3 technical replicates for each donor, with each data point representing a single donor (n = 3, B and C); data are displayed as mean ± SEM (where applicable). **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001. P values were determined by comparing treatment conditions to no-stimulation conditions for each time point. Two-way ANOVA, with Dunnett’s test for multiple comparisons (B and C).

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