Looking beyond the induction of Th2 responses to explain immunomodulation by helminths

Abstract

Although helminth infections are characteristically associated with Th2-mediated responses that include the production of the prototypical cytokines IL-4, IL-5 and IL-13 by CD4(+) cells, the production of IgE, peripheral blood eosinophilia and mucus production in localized sites, these responses are largely attenuated when helminth infections become less acute. This modulation of the immune response that occurs with chronic helminth infection is often induced by molecules secreted by helminth parasites, by non-Th2 regulatory CD4(+) cells, and by nonclassical B cells, macrophages and dendritic cells. This review will focus on those parasite- and host-mediated mechanisms underlying the modulated T-cell response that occurs as the default in chronic helminth infections.

Keywords: IL-10; IgE; IgG4; Th2 responses; alternatively activated macrophages; dendritic cells; helminths; immune modulation; innate lymphoid cells; regulatory B cells; regulatory T cells.

Figure 1

Immune responses in helminth infections as a function of time following infection. Infectious stages of helminth parasites initiate infection at barrier sites and activate a variety of different cell types such as innate lymphoid cells (ILCs), macrophages (MAC), dendritic cells (DCs), natural killer cells (NK), eosinophils (Eos) and basophils/mast cells (Baso/MC). At this relatively early phase of infection the parasite induces the differentiation of effector Th1, Th17 and Th2 cells, which together with IgE antibody, may lead to attrition of some of the parasites. At the time of patency (when egg laying/microfilarial release occurs) there is a small expansion of Th2 CD4+ cells and a concomitant contraction of Th1 cells. With the evolution of chronic longstanding infection, there is an associated expansion of IL-10- and/or TGF-β-producing regulatory T cells (Tregs). The high levels of IL-10 produced induce the production of IgG4 which together with IL-4, IL-13, and/or TGF-β induce the differentiation of alternatively activated macrophages (AAM) and inhibit the function of a variety of other cells including central memory (TCM) and effector (Teff) T cells.

Figure 2

Schematized understanding of the host response to helminth infection. Shown in blue are the characteristic mechanisms induced by the host responses (purple) or by the helminth infections/products (green) that lead to specific outcomes (red).