Research Article: IL-10- and TGFβ-mediated Th9 Responses in a Human Helminth Infection

Date Published: January 5, 2016

Publisher: Public Library of Science

Author(s): Rajamanickam Anuradha, Saravanan Munisankar, Yukthi Bhootra, Jeeva Jagannathan, Chandrakumar Dolla, Paul Kumaran, Thomas B. Nutman, Subash Babu, Abhay R Satoskar.

Abstract: BackgroundTh9 cells are a subset of CD4+ T cells that express the protoypical cytokine, IL-9. Th9 cells are known to effect protective immunity in animal models of intestinal helminth infections. However, the role of Th9 cells in human intestinal helminth infections has never been examined.MethodologyTo examine the role of Th9 cells in Strongyloidis stercoralis (Ss), a common intestinal helminth infection, we compared the frequency of Th9 expressing IL-9 either singly (mono-functional) or co-expressing IL-4 or IL-10 (dual-functional) in Ss-infected individuals (INF) to frequencies in uninfected (UN) individuals.Principal FindingsINF individuals exhibited a significant increase in the spontaneously expressed and/or antigen specific frequencies of both mono- and dual-functional Th9 cells as well as Th2 cells expressing IL-9 compared to UN. The differences in Th9 induction between INF and UN individuals was predominantly antigen-specific as the differences were no longer seen following control antigen or mitogen stimulation. In addition, the increased frequency of Th9 cells in response to parasite antigens was dependent on IL-10 and TGFx since neutralization of either of these cytokines resulted in diminished Th9 frequencies. Finally, following successful treatment of Ss infection, the frequencies of antigen-specific Th9 cells diminished in INF individuals, suggesting a role for the Th9 response in active Ss infection. Moreover, IL-9 levels in whole blood culture supernatants following Ss antigen stimulation were higher in INF compared to UN individuals.ConclusionThus, Ss infection is characterized by an IL-10- and TGFβ dependent expansion of Th9 cells, an expansion found to reversible by anti-helmintic treatment.

Partial Text: Upon antigen-specific stimulation, CD4+ T cells have the potential to differentiate into various T-helper (Th) cell subsets based on the pattern of transcription factors induced and cytokines produced [1]. Traditionally associated with the Th2 response, IL-9 is a member of the common γ chain cytokine family and exerts broad effects on many cell types including mast cells, eosinophils, T cells and epithelial cells [2,3]. However, more recently, a CD4+ T cell subset with the exclusive capacity to secrete IL-9 has been described [4,5]. This CD4+ T cell subset is thought to develop under the influence of IL-4 and TGFβ and to produce IL-9, either singly or in conjunction with IL-10; these cells fail to produce IL-4 [6,7]. However, little data are available on the expression pattern of Th9 cells in humans.

Although IL-9 is known to be expressed by several types of immune cells, IL-9 secreting CD4+ T cells are a predominant source of IL-9 in allergic inflammation and anti-parasite immunity [6,7]. Th9 cells in human diseases are known to contribute to both protective immune responses and pathological responses leading to immune mediated pathology [7]. The role of IL-9 in helminth infection was first suggested by animal studies showing that IL-9 transgenic mice infected with Trichuris muris or Trichinella spiralis had an increased Th2 response and faster expulsion of the parasite from the intestine [15,16,17]. While classically considered a Th2 cytokine, IL-9 has now been shown to produced by a distinct subset of CD4+ T cells that express IL-9 with or without IL-10 but in the absence of IL-4 [4,5]. Whether the source of IL-9 ultimately matters in the context of resistance to infection is still not clear. However, a more recent study has clearly shown that IL-9 is produced early during Nippostrongylus brasiliensis infection of mice by a non-Th2 CD4+ T cell subset and that its production from this subset is sufficient for host protection against worm infection [25].



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