title: Distinct activation thresholds of human conventional and innate-like memory T cells.
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.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Global Health, University of Washington, Seattle, Washington, USA.
authors.forename: Chloe K
authors.initials: CK
authors.lastname: Slichter
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Statistics, University of Washington, Seattle, Washington, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: McDavid
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Hannah W
authors.initials: HW
authors.lastname: Miller
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Finak
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Seymour
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: McNevin
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Diaz
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Czartoski
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Global Health, University of Washington, Seattle, Washington, USA; Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Global Health, University of Washington, Seattle, Washington, USA; Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Gottardo
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Global Health, University of Washington, Seattle, Washington, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Prlic