IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses.
CD4(+) T helper 2 (T(H)2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections. However, T(H)2 cells also promote chronic inflammation associated with asthma and allergic disorders. The non-haematopoietic-cell-derived cytokines thymic stromal lymphopoietin, IL33 and IL25 (also known as IL17E) have been implicated in inducing T(H)2 cell-dependent inflammation at mucosal sites, but how these cytokines influence innate immune responses remains poorly defined. Here we show that IL25, a member of the IL17 cytokine family, promotes the accumulation of a lineage-negative (Lin(-)) multipotent progenitor (MPP) cell population in the gut-associated lymphoid tissue that promotes T(H)2 cytokine responses. The IL25-elicited cell population, termed MPP(type2) cells, was defined by the expression of Sca-1 (also known as Ly6a) and intermediate expression of c-Kit (c-Kit(int)), and exhibited multipotent capacity, giving rise to cells of monocyte/macrophage and granulocyte lineages both in vitro and in vivo. Progeny of MPP(type2) cells were competent antigen presenting cells, and adoptive transfer of MPP(type2) cells could promote T(H)2 cytokine responses and confer protective immunity to helminth infection in normally susceptible Il25(-/-) mice. The ability of IL25 to induce the emergence of an MPP(type2) cell population identifies a link between the IL17 cytokine family and extramedullary haematopoiesis, and suggests a previously unrecognized innate immune pathway that promotes T(H)2 cytokine responses at mucosal sites.
Saenz
Steven A
SA
Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Siracusa
Mark C
MC
Perrigoue
Jacqueline G
JG
Spencer
Sean P
SP
Urban
Joseph F
JF
Tocker
Joel E
JE
Budelsky
Alison L
AL
Kleinschek
Melanie A
MA
Kastelein
Robert A
RA
Kambayashi
Taku
T
Bhandoola
Avinash
A
Artis
David
D
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D006098:Granulocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology; D018928:Immunity, Mucosal / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000276:immunology*; D009559:Nippostrongylus / Q000276:immunology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D017206:Strongylida Infections / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014257:Trichuriasis / Q000276:immunology; D014258:Trichuris / Q000276:immunology
D000950:Antigens, Ly; D007378:Interleukins; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019009:Proto-Oncogene Proteins c-kit