The Kedmi Lab

To absorb nutrients and support commensal microorganisms, the host induces tolerogenic immune responses through peripheral regulatory T (pT_reg) cells^1,2. Previous studies identified conventional type 1 dendritic cells (cDC1s) as initiators of dietary pT_reg cells³. However, here we report that food-specific pT_reg cells are induced exclusively by the recently identified RORγt antigen-presenting cells^{4, 5, 6, 78} and not by conventional dendritic cells. Instead, our data suggest that pT_reg cellcDC1 interactions during homeostasis limit the expansion of food-specific CD8αβ T cells. This regulation is disrupted by infection or food poisoning, enabling dietary CD8αβ T cells to expand and acquire effector functions in response to mimicked food antigens. Unlike in typical infections, after the pathogen is cleared, dietary CD8αβ T cells do not expand in response to their corresponding dietary antigens. Thus, we propose that, in response to dietary antigens, tolerance is mediated by a circuit of dedicated antigen-presenting cells and T cells. When the host is challenged by infection, this circuit permits the transient expansion of protective effector responses without compromising the overall strategy of tolerance that ensures safe food consumption.

The immune system recognizes a multitude of innocuous antigens from food and intestinal commensal microbes toward which it orchestrates appropriate, non-inflammatory responses. This process requires antigen-presenting cells (APCs) that induce T cells with either regulatory or effector functions. Compromised APC function disrupts the T cell balance, leading to inflammation and dysbiosis. Although their precise identities continue to be debated, it has become clear that multiple APC lineages direct the differentiation of distinct microbiota-specific CD4⁺ T cell programs. Here, we review how unique APC subsets instruct T cell differentiation and function in response to microbiota and dietary antigens. These discoveries provide new opportunities to investigate T cell-APC regulatory networks controlling immune homeostasis and perturbations associated with inflammatory and allergic diseases.

The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment ^1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohns disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (T _reg) and T follicular helper (T _FH) cells under homeostatic conditions, but induce inflammatory T helper 17 (T _H17) cells when induced T _reg (iT _reg) cells are compromised ^3,4. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iT _reg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of T _reg cells. These RORγt ⁺ cellsprobably type 3 innate lymphoid cells and/or Janus cells ⁵require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator α _v integrin. In the absence of any of these factors, there was expansion of pathogenic T _H17 cells instead of iT _reg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.