title: Autoimmune memory T helper 17 cell function and expansion are dependent on interleukin-23.
abstract: Interleukin-23 (IL-23) is essential for the differentiation of pathogenic effector T helper 17 (Th17) cells, but its role in memory Th17 cell responses is unclear. Using the experimental autoimmune encephalomyelitis (EAE) model, we report that memory Th17 cells rapidly expanded in response to rechallenge and migrated to the CNS in high numbers, resulting in earlier onset and increased severity of clinical disease. Memory Th17 cells were generated from IL-17+ and RORγt+ precursors, and the stability of the Th17 cell phenotype depended on the amount of time allowed for the primary response. IL-23 was required for this enhanced recall response. IL-23 receptor blockade did not directly impact IL-17 production, but did impair the subsequent proliferation and generation of effectors coexpressing the Th1 cell-specific transcription factor T-bet. In addition, many genes required for cell-cycle progression were downregulated in Th17 cells that lacked IL-23 signaling, showing that a major mechanism for IL-23 in primary and memory Th17 cell responses operates via regulation of proliferation-associated pathways.
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Haines
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Blumenschein
authors.forename: Renu
authors.initials: R
authors.lastname: Jain
authors.forename: Charlie
authors.initials: C
authors.lastname: Chang
authors.forename: Barbara
authors.initials: B
authors.lastname: Joyce-Shaikh
authors.forename: Katherine
authors.initials: K
authors.lastname: Porth
authors.forename: Katia
authors.initials: K
authors.lastname: Boniface
authors.forename: Jeanine
authors.initials: J
authors.lastname: Mattson
authors.forename: Beth
authors.initials: B
authors.lastname: Basham
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
authors.forename: Terrill K
authors.initials: TK
authors.lastname: McClanahan
authors.forename: Svetlana
authors.initials: S
authors.lastname: Sadekova
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cua
authors.forename: Mandy J
authors.initials: MJ
authors.lastname: McGeachy
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014184:Transplantation, Homologous; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D053759:Interleukin-23; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor