ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells.
Immune surveillance in tissues is mediated by a long-lived subset of tissue-resident memory T cells (Trm cells). A putative subset of tissue-resident long-lived stem cells is characterized by the ability to efflux Hoechst dyes and is referred to as side population (SP) cells. Here, we have characterized a subset of SP T cells (Tsp cells) that exhibit a quiescent (G0) phenotype in humans and mice. Human Trm cells in the gut and BM were enriched in Tsp cells that were predominantly in the G0 stage of the cell cycle. Moreover, in histone 2B-GFP mice, the 2B-GFP label was retained in Tsp cells, indicative of a slow-cycling phenotype. Human Tsp cells displayed a distinct gene-expression profile that was enriched for genes overexpressed in Trm cells. In mice, proteins encoded by Tsp signature genes, including nuclear receptor subfamily 4 group A member 1 (NR4A1) and ATP-binding cassette (ABC) transporters, influenced the function and differentiation of Trm cells. Responses to adoptive transfer of human Tsp cells into immune-deficient mice and plerixafor therapy suggested that human Tsp cell mobilization could be manipulated as a potential cellular therapy. These data identify a distinct subset of human T cells with a quiescent/slow-cycling phenotype, propensity for tissue enrichment, and potential to mobilize into circulation, which may be harnessed for adoptive cellular therapy.
Chandra Sekhar
CS
Boddupalli
Shiny
S
Nair
Simon M
SM
Gray
Heba N
HN
Nowyhed
Rakesh
R
Verma
Joanna A
JA
Gibson
Clara
C
Abraham
Deepak
D
Narayan
Juan
J
Vasquez
Catherine C
CC
Hedrick
Richard A
RA
Flavell
Kavita M
KM
Dhodapkar
Susan M
SM
Kaech
Madhav V
MV
Dhodapkar
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D007156:Immunologic Memory; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D016192:Resting Phase, Cell Cycle; D013601:T-Lymphocytes / Q000378:metabolism*; D059467:Transcriptome
D018528:ATP-Binding Cassette Transporters; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1