Induction of CD4+CD25+FOXP3+ Regulatory T Cells during Human Hookworm Infection Modulates Antigen-Mediated Lymphocyte Proliferation

Abstract

Hookworm infection is considered one of the most important poverty-promoting neglected tropical diseases, infecting 576 to 740 million people worldwide, especially in the tropics and subtropics. These blood-feeding nematodes have a remarkable ability to downmodulate the host immune response, protecting themselves from elimination and minimizing severe host pathology. While several mechanisms may be involved in the immunomodulation by parasitic infection, experimental evidences have pointed toward the possible involvement of regulatory T cells (Tregs) in downregulating effector T-cell responses upon chronic infection. However, the role of Tregs cells in human hookworm infection is still poorly understood and has not been addressed yet. In the current study we observed an augmentation of circulating CD4+CD25+FOXP3+ regulatory T cells in hookworm-infected individuals compared with healthy non-infected donors. We have also demonstrated that infected individuals present higher levels of circulating Treg cells expressing CTLA-4, GITR, IL-10, TGF-β and IL-17. Moreover, we showed that hookworm crude antigen stimulation reduces the number of CD4+CD25+FOXP3+ T regulatory cells co-expressing IL-17 in infected individuals. Finally, PBMCs from infected individuals pulsed with excreted/secreted products or hookworm crude antigens presented an impaired cellular proliferation, which was partially augmented by the depletion of Treg cells. Our results suggest that Treg cells may play an important role in hookworm-induced immunosuppression, contributing to the longevity of hookworm survival in infected people.

Helminth Infections and Host Immune Regulation

“…Nevertheless, it was found that hookworm-infected individuals display higher proportions of circulating CD4 ϩ CD25 ϩ Foxp3 ϩ Tregs than uninfected controls (233). In addition, among patients with intestinal nematode infections, in vitro T cell responses to malaria and mycobacterial antigens were depressed but were rescued following Treg depletion (296).…”

Relationship between Mycobacterium Tuberculosis and Hookworm Infections among School Children in Mbita, Kenya

“…+ regulatory T cells [23] and repeated infection with hookworm stimulates production of high levels of IL-10 [24], which inhibits host protective immunity against M. tuberculosis. Accordingly, there is a possibility that hookworm-induced IL-10 impacts on the sensibility to M. tuberculosis infection.…”

Mycobacterium tuberculosis‐specific CD4+ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

“…These cells are able to control both Th2 and Th1 type immune responses [17]. Helminth infection can increase the frequency of Treg cells in mice [18,19], and in man an increase of Treg cells has been observed in Strongyloides infection in patients coinfected with HTLV-1 [20] as well as in hookworm-infected patients [21]. Furthermore, it has been shown that Treg cells can modulate the immune response in Mycobacterium bovis bacille Calmette-Guerin (BCG)-vaccinated individuals [22,23] and in patients with active TB [24].…”