title: Regulatory T cells limit induction of protective immunity and promote immune pathology following intestinal helminth infection.
abstract: Foxp3(+) regulatory T cells (Tregs) have a well-characterized role in limiting autoimmunity and dampening deleterious immune responses. However, a potential consequence of the immunosuppressive function of Tregs can be the limitation of protective immunity to infectious pathogens. Parasitic infections are a potent stimulus for the generation of Treg responses, which may be beneficial to both the parasite and the host by promoting persistence of infection and limiting immune-mediated pathology, respectively. In this study, we explore the functional role of Tregs post-low-dose infection with the intestinal helminth parasite Trichuris muris, which yields a chronic infection because of inefficient induction of Th2 responses. Early Treg depletion postinfection resulted in expedited worm clearance, and was associated with reduced Th1-mediated inflammation of the intestinal environment. Interestingly, this protective immunity was lost, and worm burden enhanced if Tregs were depleted later once the infection was established. Early and late Treg depletion resulted in enhanced Th2 and reduced Th1 cytokine and humoral responses. Blockade of the Th2 cytokine IL-4 resulted in a moderate increase in Th1 but had no effect on worm burden. Our findings suggest that Tregs preferentially limit Th2 cell expansion, which can impact infections where clear immune polarity has not been established. Thus, the impact of Treg depletion is context and time dependent, and can be beneficial to the host in situations where Th1 responses should be limited in favor of Th2 responses.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Deepali V
authors.initials: DV
authors.lastname: Sawant
authors.forename: David M
authors.initials: DM
authors.lastname: Gravano
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: Paul
authors.initials: P
authors.lastname: Giacomin
authors.forename: David
authors.initials: D
authors.lastname: Artis
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D000909:Antibodies, Helminth / Q000097:blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D007422:Intestines / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014257:Trichuriasis / Q000097:blood / Q000276:immunology* / Q000469:parasitology; D014258:Trichuris / Q000276:immunology* / Q000502:physiology
chemical_list: D000909:Antibodies, Helminth; D016207:Cytokines; D004167:Diphtheria Toxin; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007074:Immunoglobulin G; D015847:Interleukin-4; D007371:Interferon-gamma