Helminth-Induced Production of TGF-β and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells

Abstract

Helminths stimulate the secretion of T helper 2 (Th2) cytokines, like interleukin-4 (IL4) and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). This suppression depends on the production of immune-modulatory TGFβ and is associated with TGFβ-dependent in vivo expansion of Foxp3+ regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGFβ-dependent, in vivo expansion of Tregs - in a Th2 polarized environment after helminth infection - is unknown. Here we show that helminth-induced IL4 production by host cells is critical to the induction and maintenance of TGFβ secretion, TGFβ-dependent expansion of Foxp3+ Tregs, and the suppression of GVHD. In mice with GVHD, the expanding donor Tregs express the Th2-driving transcription factor, GATA3, which is required for helminth-induced production IL4 and TGFβ. On the other hand, TGFβ is not necessary for GATA3 expression by Foxp3+ Tregs or by Foxp3− CD4 T cells. Various cell types of innate or adaptive immune compartments produce high quantities of IL4 after helminth infection. As a result, IL4-mediated suppression of GVHD does not require invariant NKT (iNKT) cells of the host - a cell type known to produce IL4 and suppress GVHD in other models. Thus, TGFβ generation – in a manner dependent on IL4 secretion by host cells and GATA3 expression - constitutes a critical effector arm of helminthic immune modulation that promotes the in vivo expansion of Tregs and suppresses GVHD.

Impact of Helminth Infections on Female Reproductive Health and Associated Diseases

“…Furthermore, Johnston et al (42) demonstrated the suppression of skin allograft rejection by treatment with a TGF-b mimic isolated from HES (42). In support, Li et al (64) demonstrated suppression of allograft rejection with H. polygyrus-induced Th2 and regulatory T cell bystander immunity (64). Recombinant hookworm anti-inflammatory proteins have been shown to reduce inflammation during experimental colitis (65) and asthma (66), associated with the induction of regulatory T cells.…”

The Anti-Inflammatory Immune Response in Early Trichinella spiralis Intestinal Infection Depends on Serine Protease Inhibitor–Mediated Alternative Activation of Macrophages

“…In short, natural Ts-serpin induced the upregulation of antiinflammatory cytokines and inhibited the level of proinflammatory cytokines in mLNs and peritoneal cells. According to classical immune theory, increasing levels of anti-inflammatory cytokines are thought to directly induce immunosuppression and are the main strategy for identifying target immune cells with which proteins interact (49,50). The secretion of anti-inflammatory cytokines is mainly derived from alternatively activated macrophages or Tregs (4,51,52).…”

Identification of Chlorophyll a-b Binding Protein AB96 as a novel TGFβ1 binding agent

“…This can be seen to correlate with the induction of Tregs 11 , which facilitate plasmodium growth 12 , indeed it is worth noting at this point that individuals of Fulani heritage in West Africa frequently carry a mutation which prevents Treg induction and have reduced susceptibility to P. falciparum infection 13 . In intestinal helminth infection, TGFβ1 is induced and activated by the parasite inducing a profound increase in Tregs 14 , to such an extent that controlled infection is being trialed for a number of autoimmune diseases including Graft versus Host Disease (GvHD) 15 . Interestingly, beyond TGFβ1 induction and activation within the host, it has recently been shown that the helminth, H. Polygyrus , produces its own functional TGFβ1 mimetic 16 .…”