title: ECM components guide IL-10 producing regulatory T-cell (TR1) induction from effector memory T-cell precursors.
abstract: We describe a role for ECM as a biosensor for inflammatory microenvironments that plays a critical role in peripheral immune tolerance. We show that hyaluronan (HA) promotes induction of Foxp3- IL-10-producing regulatory T cells (TR1) from conventional T-cell precursors in both murine and human systems. This is, to our knowledge, the first description of an ECM component inducing regulatory T cells. Intact HA, characteristic of healing tissues, promotes induction of TR1 capable of abrogating disease in an IL-10-dependent mouse colitis model whereas fragmentary HA, typical of inflamed tissues, does not, indicating a decisive role for tissue integrity in this system. The TR1 precursor cells in this system are CD4(+)CD62L(-)FoxP3(-), suggesting that effector memory cells assume a regulatory phenotype when they encounter their cognate antigen in the context of intact HA. Matrix integrity cues might thereby play a central role in maintaining peripheral tolerance. This TR1 induction is mediated by CD44 cross-linking and signaling through p38 and ERK1/2. This induction is suppressed, also in a CD44-dependent manner, by osteopontin, a component of chronically inflamed ECM, indicating that CD44 signaling serves as a nexus for fate decisions regarding TR1 induction. Finally, we demonstrate that TR1 induction signals can be recapitulated using synthetic matrices. These results reveal important roles for the matrix microenvironment in immune regulation and suggest unique strategies for immunomodulation.
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA. pbollyky@benaroyaresearch.org
authors.forename: Paul L
authors.initials: PL
authors.lastname: Bollyky
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Wu
authors.forename: Ben A
authors.initials: BA
authors.lastname: Falk
authors.forename: James D
authors.initials: JD
authors.lastname: Lord
authors.forename: S Alice
authors.initials: SA
authors.lastname: Long
authors.forename: Anton
authors.initials: A
authors.lastname: Preisinger
authors.forename: Brandon
authors.initials: B
authors.lastname: Teng
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Holt
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Standifer
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Braun
authors.forename: Cindy Fang
authors.initials: CF
authors.lastname: Xie
authors.forename: Peter L
authors.initials: PL
authors.lastname: Samuels
authors.forename: Robert B
authors.initials: RB
authors.lastname: Vernon
authors.forename: John A
authors.initials: JA
authors.lastname: Gebe
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003092:Colitis / Q000276:immunology; D005109:Extracellular Matrix / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology; D006820:Hyaluronic Acid / Q000276:immunology; D007156:Immunologic Memory; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053495:Osteopontin / Q000276:immunology; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C476399:Cd44 protein, mouse; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; C556062:IL10 protein, mouse; D007376:Interleukin-2; C506896:Spp1 protein, mouse; D053495:Osteopontin; C064658:RAG-1 protein; D016753:Interleukin-10; D006820:Hyaluronic Acid