Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

Abstract

One third of the human population is infected with helminth parasites. To promote their longevity and to limit pathology, helminths have developed several strategies to suppress the immune response of their host. As this immune suppression also acts on unrelated third-party Ags, a preexisting helminth infection may interfere with vaccination efficacy. In this study, we show that natural infection with Litomosoides sigmodontis suppressed the humoral response to thymus-dependent but not to thymus-independent model Ags in C57BL/6 mice. Thereby, we provide evidence that reduced humoral responses were mediated by interference with Th cell function rather than by direct suppression of B cells in L. sigmodontis-infected mice. We directly demonstrate suppression of Ag-specific proliferation in OVA-specific Th cells after adoptive transfer into L. sigmodontis-infected mice that led to equally reduced production of OVA-specific IgG. Transferred Th cells displayed increased frequencies of Foxp3+ after in vivo stimulation within infected but not within naive mice. Helminth-mediated suppression was induced by established L. sigmodontis infections but was completely independent of the individual worm burden. Using DEREG mice, we rule out a central role for host-derived regulatory T cells in the suppression of transferred Th cell proliferation. In contrast, we show that L. sigmodontis-induced, host-derived IL-10 mediated Foxp3 induction in transferred Th cells and significantly contributed to the observed Th cell hypoproliferation within infected mice.

Nematode-Induced Interference with Vaccination Efficacy Targets Follicular T Helper Cell Induction and Is Preserved after Termination of Infection

“…However, in the current study we show that suppression of IgG response during chronic infection of BALB/c mice was clearly established in the absence of Foxp3 + T reg. This suggests that immune modulation during acute and chronic L. sigmodontis infection in C57BL/6 and BALB/c mice is established by similar mechanisms such as IL-10 induction [31]. Potential mediators of suppression in addition to Foxp3 + T reg are IL-10 producing Foxp3 − T cells [50], IL-10 producing regulatory B cells [51], [52], alternatively activated macrophages [53], and tolerogenic dendritic cells [54] that have been shown to mediate suppression during nematode infection in several murine systems.…”

“…Suppression of OT-II T cell proliferation during acute L. sigmodontis -infection of C57BL/6 mice was shown to be T reg -independent and partially mediated by IL-10 [31]. Early depletion of CD4 + CD25 + T reg improved host defence in L. sigmodontis -infected BALB/c mice, suggesting an implication of T reg in immune evasion for this genetic background [36].…”

Effect of helminth-induced immunity on infections with microbial pathogens

“…In contrast, a negative regulatory regime imposed by the population expansion and activation of T reg cells might have a more prominent role in restricting the function of preformed effector memory and effector T cells located at peripheral tissue sites. Another study has also suggested the deviation of T H 1 cells into Foxp3 + regulatory cells mediated by helminth-induced production of IL-10, rather than T reg cell–mediated downmodulation itself, as the underlying mechanism for the diminished T H 1 responses to vaccination 116 . A similar mechanism of localized recruitment of Foxp3 + T reg cells may be involved in the exertion of anti-inflammatory effects by IL-10-producing regulatory B cells induced by helminth infection 117 .…”

Helminth Infections Decrease Host Susceptibility to Immune-Mediated Diseases

“…As with Hpb infection (15), other helminthic species like Hymenolepis diminuta (16) and Schistosoma mansoni (17) also induce IL10 secretion. Litomosoides sigmodontis suppressed B cells responses in the host through induction of IL10 and Tregs (18, 19). …”