Antigen-specific cellular hyporesponsiveness in a chronic human helminth infection is mediated by T(h)3/T(r)1-type cytokines IL-10 and transforming growth factor-beta but not by a T(h)1 to T(h)2 shift.
Exposure to infective larvae of the filarial nematode Onchocerca volvulus (Ov) either results in patent infection (microfilaridermia) or it leads to a status called putative immunity, characterized by resistance to infection. Similar to other chronic helminth infections, there is a T cell proliferative hyporesponsiveness to Ov antigen (OvAg) by peripheral blood mononuclear cells (PBMC) from individuals with patent infection, i.e. generalized onchocerciasis (GEO), compared to PBMC from putatively immune (PI) individuals. In this study, mechanisms mediating this cellular hyporesponsiveness in GEO were investigated: the low proliferative response in PBMC from GEO individuals was associated with a lack of IL-4 production and significantly lower production of IL-5 compared to those from PI individuals, arguing against a general shift towards a T(h)2 response being the cause of hyporesponsiveness. In contrast, IL-10 and transforming growth factor (TGF)-beta, two cytokines associated with a T(h)3 response, seemed to mediate hyporesponsiveness: PBMC from individuals with GEO produced significantly more IL-10, and T cell proliferative hyporesponsiveness in this group could be reversed by the addition of anti-IL-10 and anti-TGF-beta antibodies. Hyporesponsiveness was specific for OvAg and not observed upon stimulation with related nematode antigens, arguing for a T cell-mediated, Ov-specific down-regulation. Ov-specific T cells could be cloned from GEO PBMC which have a unique cytokine profile (no IL-2 but high IL-10 and/or TGF-beta production), similar to the T cell subsets known to suppress ongoing inflammation (T(h)3 and T(r)1), indicating that this cell type which has not been found so far in infectious diseases may be involved in maintaining Ov-specific hyporesponsiveness.
Doetze
A
A
Bernhard Nocht Institute of Tropical Medicine, 20359 Hamburg, Germany.
Satoguina
J
J
Burchard
G
G
Rau
T
T
Löliger
C
C
Fleischer
B
B
Hoerauf
A
A
D000818:Animals; D000947:Antigens, Helminth / Q000494:pharmacology; D002478:Cells, Cultured; D002908:Chronic Disease; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007111:Immunity, Cellular; D016753:Interleukin-10 / Q000032:analysis / Q000276:immunology*; D015847:Interleukin-4 / Q000032:analysis; D015848:Interleukin-5 / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D017181:Onchocerca volvulus / Q000276:immunology; D009855:Onchocerciasis / Q000276:immunology* / Q000469:parasitology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000276:immunology*
D000947:Antigens, Helminth; D015848:Interleukin-5; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4