title: IL-23-dependent IL-17 drives Th1-cell responses following Mycobacterium bovis BCG vaccination.
abstract: The generation of effective type 1 T helper (Th1)-cell responses is required for immunity against intracellular bacteria. However, some intracellular bacteria require interleukin (IL)-17 to drive Th1-cell immunity and subsequent protective host immunity. Here, in a model of Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccination in mice, we demonstrate that the dependence on IL-17 to drive Th1-cell responses is a host mechanism to overcome bacteria-induced IL-10 inhibitory effects. We show that BCG-induced prostaglandin-E2 (PGE2) promotes the production of IL-10 which limits Th1-cell responses, while simultaneously inducing IL-23 and Th17-cell differentiation. The ability of IL-17 to downregulate IL-10 and induce IL-12 production allows the generation of subsequent Th1-cell responses. Accordingly, BCG-induced Th17-cell responses precede the generation of Th1-cell responses in vivo, whereas the absence of the IL-23 pathway decreases BCG vaccine-induced Th17 and Th1-cell immunity and subsequent vaccine-induced protection upon M. tuberculosis challenge. Importantly, in the absence of IL-10, BCG-induced Th1-cell responses occur in an IL-17-independent manner. These novel data demonstrate a role for the IL-23/IL-17 pathway in driving Th1-cell responses, specifically to overcome IL-10-mediated inhibition and, furthermore, show that in the absence of IL-10, the generation of BCG-induced Th1-cell immunity is IL-17 independent.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Radha
authors.initials: R
authors.lastname: Gopal
authors.forename: Yinyao
authors.initials: Y
authors.lastname: Lin
authors.forename: Nataša
authors.initials: N
authors.lastname: Obermajer
authors.forename: Samantha
authors.initials: S
authors.lastname: Slight
authors.forename: Nikhil
authors.initials: N
authors.lastname: Nuthalapati
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Ahmed
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.forename: Shabaana A
authors.initials: SA
authors.lastname: Khader
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000235:genetics; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D056747:Immunomodulation; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009163:Mycobacterium bovis / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D019899:Paracrine Communication / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014376:Tuberculosis / Q000276:immunology*; D014611:Vaccination
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D016753:Interleukin-10; D007371:Interferon-gamma; D015232:Dinoprostone
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