Regulatory T Cells in Human Lymphatic Filariasis: Stronger Functional Activity in Microfilaremics

Abstract

Infection with filarial parasites is associated with T cell hyporesponsiveness, which is thought to be partly mediated by their ability to induce regulatory T cells (Tregs) during human infections. This study investigates the functional capacity of Tregs from different groups of filarial patients to suppress filaria-specific immune responses during human filariasis. Microfilaremic (MF), chronic pathology (CP) and uninfected endemic normal (EN) individuals were selected in an area endemic for Brugia timori in Flores island, Indonesia. PBMC were isolated, CD4CD25hi cells were magnetically depleted and in vitro cytokine production and proliferation in response to B. malayi adult worm antigen (BmA) were determined in total and Treg-depleted PBMC. In MF subjects BmA-specific T and B lymphocyte proliferation as well as IFN-gamma, IL-13 and IL-17 responses were lower compared to EN and CP groups. Depletion of Tregs restored T cell as well as B cell proliferation in MF-positives, while proliferative responses in the other groups were not enhanced. BmA-induced IL-13 production was increased after Treg removal in MF-positives only. Thus, filaria-associated Tregs were demonstrated to be functional in suppressing proliferation and possibly Th2 cytokine responses to BmA. These suppressive effects were only observed in the MF group and not in EN or CP. These findings may be important when considering strategies for filarial treatment and the targeted prevention of filaria-induced lymphedema.

Environmental Hygiene and Risk of Inflammatory Bowel Diseases

“…Other mechanisms proposed include antigenic competition and influence on regulatory T-cell function 6, 40 ; for example newborns of mothers exposed to farming demonstrate up-regulation of regulatory T cells 42 . Patients in parasite endemic areas have high levels of IL-10 and regulatory T-cell activity and lower levels of pro-inflammatory cytokines 43, 44 . A third mechanism may be through modification of the gut microbiome.…”

Regulation of the host immune system by helminth parasites

“…In human subjects Treg cells expressing the transcription factor forkhead box protein 3 (Foxp3) are more numerous and more active in helminth-infected subjects but decrease after anthelmintic chemotherapy 19, 34, 35. In filarial infections patients with pathologies, such as elephantiasis and hyperreactive onchocerciasis, show diminished Treg cell levels compared with those in unresponsive asymptomatic carriers, supporting the argument that the Treg cell compartment both maintains tolerance and prevents pathology in these infections 15, 36, 37.…”

Helminth Infections and Host Immune Regulation

“…It was suggested that CTLA-4 (and PD-1 [programmed cell death 1]) may be involved in blocking inflammatory bystander responses in infected patients (13). Recently, regulatory T cells from microfilaremic individuals, but not those from uninfected individuals, were shown to suppress both Th1 and Th2 peripheral blood mononuclear cell (PBMC) cytokine production, providing further evidence of a link between Tregs and the hyporesponsive state (297). In contrast, PBMCs from filaria-infected individuals with chronic pathology fail to upregulate Foxp3 in response to filarial antigen, potentially indicating that Tregs are deficient in these patients (14), although this is subject to the caveat that Foxp3 can also be activation induced in humans (298).…”