Transmission intensity determines lymphocyte responsiveness and cytokine bias in human lymphatic filariasis

Humans living in areas where filariasis is endemic vary greatly in their ex posure to mosquito-borne infective third-stage larvae (L3) of these parasit ic helminths. Because the intensity of exposure to Ags affects T cell diffe rentiation and susceptibility to parasitic infections in murine models, we compared T cell and cytokine responses in 97 residents of two villages in P apua New Guinea, where transmission intensity of Wuchereria bancrofti diffe red by 63-fold (37 vs 2355 L3 per person per year). Residents of the high t ransmission village had 4- to 11-fold lower proliferation and IFN-gamma res ponses to filarial Ags, nonparasite Ag, and PHA by PBMC compared with the l ow transmission village (p < 0.01) even when subjects were matched for inte nsity of infection. In contrast, filarial Ag-driven IL-5 production was 5.5 -fold greater (p < 0.001), and plasma IL-4 and TGF-beta levels were 4-fold and 34% higher, respectively, in residents of the high transmission village . IL-4 and IL-10 responses by PBMC differed little according to village, an d increased production of the counterregulatory cytokines IL-10 or TGF-beta by PBMC did not correlate with weak proliferation and IFN-gamma responses. Plasma IL-5, IFN-gamma, and IL-10 levels were similar in the two villages. These data demonstrate that the intensity of exposure to L3 affects lympho cyte responsiveness and cytokine bias possibly by a mechanism that alters A PC function.