Immune tolerance to foreign antigens in the intestine: mechanisms mediated by CD4＋ T cells

Abstract

The immune system encounters a diverse array of antigens, both self and foreign, necessitating mechanisms to maintain tolerance and prevent harmful inflammatory responses. CD4＋ T cells, crucial in orchestrating immune responses, play a critical role in mediating tolerance to both self and foreign antigens. While the mechanisms of CD4＋ T cell-mediated tolerance to self-antigens are well-documented, the understanding of tolerance to foreign antigens, including those from commensal microbes and food, remains incomplete. This review discusses recent progress in the mechanisms underlying immune tolerance to foreign antigens, with a focus on the role of CD4＋ T cells. We explore how inflammatory and tolerogenic CD4＋ T cell subsets are developed and maintained. Moreover, we delve into the complexities of immune responses to commensal microbes and food antigens by reviewing recent findings, highlighting the immunological contexts that shape immune tolerance. Understanding these mechanisms enhances our comprehension of how immune tolerance is established and sustained, providing insights into potential therapeutic approaches for managing chronic inflammatory diseases resulting from a loss of immune tolerance to foreign antigens. [BMB Reports 2025; 58(4): 158-168].

Fig. 1

CD4⁺ T cell differentiation: T helper subsets. CD4⁺ T cells have the potential to differentiate into diverse Th subsets. In addition to TCR-mediated and costimulatory signals, cytokine-mediated signals also direct the differentiation of naive CD4⁺ T cells into subsets such as Th1, Th2, Th17, Tfh, and Treg cells. Th1, Th2, and Th17 cells are inflammatory subsets that play crucial roles in defending against pathogens. Tfh cells enhance B cell responses, promoting the production of high-quality antibodies, while Treg cells suppress immune responses to maintain tolerance. TCR, T cell receptor; Th, T helper; Tfh, T follicular helper; tTreg, thymic regulatory T; pTreg, peripheral regulatory T.

Fig. 2

Immune response to commensal microbes. The immune system actively responds to commensal microbes in the intestine. Under normal conditions, Foxp3-expressing Treg cells are generated in response to microbes such as Helicobacter hepaticus and Bacteroides fragilis. Additionally, non-Treg populations, including Tfh cells and IL-10-producing Th17 cells, are induced by Akkermansia muciniphila and segmented filamentous bacteria (SFB). Although these immune responses generally promote tolerance to commensal microbes, Th1-like RORγt⁺ Th17 cells can drive inflammation in response to H. hepaticus in the absence of IL-10 or an adaptive immune system. Treg, regulatory T; Tfh, T follicular helper; Th, T helper.

Fig. 3

Immune response to food antigens. The immune system predominantly generates tolerogenic responses to ingested food antigens. In the presence of commensal microbes, immunosuppressive Treg cells and dysfunctional anergic cells, or Th^lin- cells in a dysfunctional state, which are negative for all markers for conventional T helper cells, are induced in response to the protein components of food. These cell types mediate immune tolerance and maintain hyporesponsiveness to ingested food antigens. Conversely, when the commensal microbiota is disrupted, CD4⁺ T cells differentiate into Th2-like Tfh cells, which promote the production of IgE against food antigens, potentially leading to allergic reactions. Treg, regulatory T; Tfh, T follicular helper; Th^lin-, T helper lineage negative.