title: IL-15-dependent upregulation of GITR on CD8 memory phenotype T cells in the bone marrow relative to spleen and lymph node suggests the bone marrow as a site of superior bioavailability of IL-15.
abstract: CD8 memory T cells are enriched in the bone marrow, a site where these cells are thought to receive homeostatic signals. However, the primary site where CD8 memory T cells receive their cytokine-induced homeostatic signals has recently come under debate. In this study, we demonstrate that the bone marrow contains a fraction of CD8 memory phenotype T cells with elevated expression of glucocorticoid-induced TNFR-related protein (GITR). In contrast, splenic and lymph node memory phenotype T cells have GITR levels similar to those on naive T cells. The bone marrow GITR(hi) memory T cells have a phenotype indicative of cytokine activation, with higher CD122 and lower CD127 than do the GITR(basal) memory T cells. Remarkably, these bone marrow-specific GITR(hi) cells are almost completely ablated in the absence of IL-15, whereas TNFR2 and 4-1BB expression on the CD8 memory T cells are IL-15 independent. Furthermore, adoptively transferred splenic CD8 memory phenotype T cells show IL-15-dependent GITR upregulation upon entry into the bone marrow. This result implies that the selective appearance of GITR(hi) memory phenotype T cells in the bone marrow reflects the local microenvironment rather than a different subset of memory T cells. GITR(-/-) mice have a lower frequency of CD8 memory phenotype cells in the bone marrow, yet the GITR(-/-) cells hyperproliferate compared with those in wild-type mice. Taken together, these data suggest that GITR plays a role in the survival of CD8 memory phenotype T cells and that GITR upregulation represents a precise marker of cells that have responded to IL-15.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Snell
authors.forename: Gloria H Y
authors.initials: GH
authors.lastname: Lin
authors.forename: Tania H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001853:Bone Marrow / Q000276:immunology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000276:immunology* / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; D019409:Interleukin-15; C106544:Tnfrsf18 protein, mouse