Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasite persistence.
Patent lymphatic filariasis is characterized by a profound down-regulation of immune responses with both parasite Ag-specific tolerance and bystander suppression. Although this down-regulation is confined to the Th1 arm of the immune system in response to parasite Ag, we hypothesized a more generalized suppression in response to live parasites. Indeed, when we examined the cytokine profile of a cohort of filaria-infected (n = 10) and uninfected (n = 10) individuals in response to live infective-stage larvae or microfilariae of Brugia malayi, we found significant impairment of both Th1 and Th2 cytokines characterized by diminished production of IFN-gamma, TNF-alpha, IL-4, IL-5, and IL-10 in infected patients. The molecular basis of this impaired Th1/Th2 response was examined, and we identified three major networks of immunoregulation and tolerance. First, impaired induction of T-bet and GATA-3 mRNA underlies the Th1/Th2 deficiency in infected individuals. Second, regulatory networks, as evidenced by significantly increased expression of Foxp3 (natural regulatory T cell marker) and regulatory effectors such as TGF-beta, CTLA-4, PD-1, ICOS, and indoleamine 2,3-dioxygenase play an important role in immunosuppression. Third, the compromise of effector T cell function is mediated by the enhanced induction of anergy-inducing factors cbl-b, c-cbl (cbl is abbreviation for Casitas B lymphoma), Itch, and Nedd4. Indeed, blocking CTLA-4 or neutralizing TGF-beta restored the ability to mount Th1/Th2 responses to live parasites and reversed the induction of anergy-inducing factors. Hence, we conclude that a profound impairment of live parasite-specific Th1 and Th2 immune responses occurs in lymphatic filariasis that is governed at the transcriptional level by a complex interplay of inhibitory mediators.
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. sbabu@niaid.nih.gov
Subash
S
Babu
Carla P
CP
Blauvelt
V
V
Kumaraswami
Thomas B
TB
Nutman
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism; D017178:Brugia malayi / Q000254:growth & development* / Q000276:immunology*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D004605:Elephantiasis, Filarial / Q000276:immunology* / Q000469:parasitology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D050990:GATA3 Transcription Factor / Q000037:antagonists & inhibitors; D006790:Host-Parasite Interactions / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors; D000098815:T-bet Transcription Factor
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D044767:Ubiquitin-Protein Ligases