T Follicular Helper Cell–Derived IL-4 Is Required for IgE Production during Intestinal Helminth Infection

Abstract

IgE production plays a crucial role in protective as well as pathogenic type 2 immune responses. Although the cytokine IL-4 is required for the development of IgE-producing plasma cells, the source of IL-4 and cellular requirements for optimal IgE responses remain unclear. Recent evidence suggests that T follicular helper (Tfh) cells are the primary producer of IL-4 in the reactive lymph node during type 2 immune responses. As Tfh cells are also required for the development of plasmablasts derived from germinal center and extrafollicular sources, we hypothesized that this cell subset is essential for the IgE plasmablast response. In this study, we show that during intestinal helminth infection, IL-4 derived from Tfh cells is required for IgE class switching and plasmablast formation. Notably, early IgE class switching did not require germinal center formation. Additionally, Tfh cell-derived IL-4 was required to maintain the Th2 response in the mesenteric lymph nodes of infected mice. Collectively, our results indicate that IL-4-producing Tfh cells are central orchestrators of the type 2 immune response in the reactive lymph nodes during parasitic helminth infection.

The Transcription Factor Ets1 Suppresses T Follicular Helper Type 2 Cell Differentiation to Halt the Onset of Systemic Lupus Erythematosus

“…However, Tfh17 and Tfh2 cells are yet to be described in murine systems. There are, however, a plethora of reports regarding IL-4-producing Tfh cells in the context of B cell activation, IgE class switching, anti-helminth immunity, and asthma, and these cells could be considered murine versions of Tfh2 cells (Kobayashi et al, 2016;Meli et al, 2017;Reinhardt et al, 2009;Weinstein et al, 2016;Yusuf et al, 2010). Nevertheless, in contrast to human Tfh2 cells, the IL-4 + Tfh cells examined in these reports do not express GATA-3.…”

Regulation of IgE by T follicular helper cells

“…Recent experiments using mice with conditional loss of Bcl6 or IL‐6 receptor signaling in T cells, which abrogates Tfh cell development, showed that Tfh cells are critical for inducing IgE in multiple type 2 responses including to allergens . Further, bone marrow chimera experiments that isolated IL‐4 deficiency to Tfh cells also demonstrated severely reduced IgE responses, suggesting that Tfh cell‐derived IL‐4 is the main driver of IgE in vivo . Supporting these findings of the importance of Tfh cells in directing IgE responses, a functional dichotomy between Th2 and Tfh cells in regulating peripheral inflammation and IgE, respectively, has begun to emerge.…”

“…Based on the recent evidence, the model that emerges for IgE induction is that IL‐4‐producing Tfh cells drive IgE responses . However, allergens typically induce high‐affinity anaphylactic IgE responses, which are rarely induced during helminth infections as previously discussed.…”

Indoor dust acts as an adjuvant to promote sensitization to peanut through the airway

“…Through the secretion of IL‐4 and IL‐13, Th2 cells promote allergen‐specific IgE production by B cells . Although Th2 cells have historically been considered the primary mediators of allergic sensitization, there is growing evidence that T follicular helper (Tfh) cells also play a critical role in promoting IgE production . Through their ability to provide help to germinal centre B cells, Tfh cells promote antibody isotype class switching and B cell differentiation into plasma and memory cells .…”

“…25 Although Th2 cells have historically been considered the primary mediators of allergic sensitization, there is growing evidence that T follicular helper (Tfh) cells also play a critical role in promoting IgE production. 15,[26][27][28] Through their ability to provide help to germinal centre B cells, Tfh cells promote antibody isotype class switching and B cell differentiation into plasma and memory cells. 29 Accordingly, recent studies have shown that Tfh cells are essential for the development of IgE responses against inhaled antigens.…”