The Differentiation of CD4(+) T-Helper Cell Subsets in the Context of Helminth Parasite Infection

Abstract

Helminths are credited with being the major selective force driving the evolution of the so-called "type 2" immune responses in vertebrate animals, with their size and infection strategies presenting unique challenges to the immune system. Originally, type 2 immune responses were defined by the presence and activities of the CD4(+) T-helper 2 subset producing the canonical cytokines IL-4, IL-5, and IL-13. This picture is now being challenged by the discovery of a more complex pattern of CD4(+) T-helper cell subsets that appear during infection, including Tregs, Th17, Tfh, and more recently, Th22, Th9, and ThGM. In addition, a clearer view of the mechanisms by which helminths and their products selectively prime the CD4(+) T-cell subsets is emerging. In this review, we have focused on recent data concerning the selective priming, differentiation, and functional role of CD4(+) T-helper cell subsets in the context of helminth infection. We argue for a re-evaluation of the original Th2 paradigm and discuss how the observed plasticity of the T-helper subsets may enable the parasitized host to achieve an appropriate compromise between elimination, tissue repair, containment, and pathology.

Keywords: CD4 T cells; TfH; Th17; Th2; Th9; differentiation; helminth.

Figure 1

Proposed models of Th2 differentiation induced by helminth parasite antigens presented by DC. (A) Antigen taken up by DC is presented to specific CD4 + T-cells. Low-avidity interactions between CD4 + T-cell and DC result in the priming of Th2 cells, whereas high avidity interactions result in the priming of Th1 or Th17 cells. (B) DC conditioned by parasite-induced innate cytokines/cells, or directly conditioned by parasite products, acquire the ability to prime Th2 responses. Th1 and/or Th17 responses are initiated by DC conditioned by other innate signals. (C) A specific DC subset that is uniquely able to take up parasite material is programed to prime Th2 immune responses. The priming of other T-cell phenotypes requires other DC subsets.

Figure 2

Dynamic of T helper differentiation. (A) The dynamic of T helper differentiation can be visualized as a “potential landscape” in which each T helper subset represent a stable position or “valley” and the transition from one subset to another, would be a “hill”, difficult to pass. Initially, the transition state between T helper subsets was considered as instable, and thus not observable in vivo. However, Th1/Th2 hybrid population has recently been reported to be stable after helminth infection. As this hybrid state is less abundant than Th1 or Th2, one could presume that the hybrid population is less stable that the Th1 or Th2 subsets, thus represented as a less deep well. (B) This transition between subsets can be further defined by the ration of transcription factor participating in the fate determination of each subset. For example, the Th1/Th2 population has been shown to present intermediary level of gata-3 and T-bet expression as compared respectively to Th2 and Th1. Through similar transcriptomic approach, generalised on all the T helper subsets, it would thus be possible to define a ration of transcription factors necessary to enable the switch from one subset to another. (C) The plasticity of the T helper subsets is represented in a conceptual 3D potential landscape and illustrate that the diverse repertoire of T helper cell subsets, and its important plasticity, enable the host to have an array of fine-tuned adaptive responses to both control the parasite development and avoid and repair pathology caused by the worm migration.

Figure 3

Evolution of the view on T helper involvement in helminth infection. By taking into account all the other T helper subset known to date, it is proposed that an immune response against on helminth can be summarized as a 2D map defined by an axis of susceptibility/protection and an axis of pathology/damage control. For an optimal response against a parasite, the host would thus mount a Th2/Th9 response with a low Tregs response and almost not existing Th1, Th17 response. The Th2 arm of the immune response protects against helminth by expanding ILCs, eosinophils and basophils all involved in parasite expulsion or by activating macrophages in AAM, playing a role in granuloma formation. Th9 rather protects by increasing goblet cells hyperplasia and muscle contractility in the gut. Th17 induced pathology is mainly mediated by neutrophils and inflammatory macrophages. In contrary, Tregs induced development of regulatory macrophages, which control pathology.