Biology subjects

Kedmi, R.

Publications and source records attributed to Kedmi, R..

3 recordsLinked to original sources

bioRxiv2024

Coordinated network of T cells and antigen presenting cells regulate tolerance to food

To efficiently absorb nutrients and facilitate microbial commensalism, the host establishes tolerogenic immune programs against dietary and commensal antigens, promoted by peripheral regulatory T cells (pTregs)1,2. Previous research into which antigen-presenting cells (APCs) initiate dietary pTreg responses focused on type 1 DCs (cDC1)3. However, we now report that food-specific pTreg cells are exclusively induced by the recently identified ROR{gamma}t+ APCs4-8, and not by cDC1. Instead, pTregs interact with cDC1 to regulate the response of food-specific CD8{beta} T cells that accumulate in the lamina propria (LP) and epithelial layer of the small intestine (SI) and express memory markers. Upon infection with pathogens that mimic dietary antigens, food-specific CD8{beta} cells activate an effector program to potentially guard against Trojan horse attacks. Uniquely, after the infection resolves, these cells do not respond to their corresponding dietary antigens, allowing for safe food consumption. Based on our findings, we propose that in response to dietary antigens, dedicated antigen-presenting cells direct a unique CD8{beta} response that is coupled to the pTreg program to facilitate protective acute effector responses within the overall strategy of tolerance.

immunology↗

bioRxiv2021

Antigen presentation by type 3 innate lymphoid cells instructs the differentiation of gut microbiota-specific regulatory T cells

The mutualistic relationship of gut-resident microbiota and cells of the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a poised, but largely non-aggressive, immune cell compartment1, 2. Consequences of disturbing this balance, by environmental or genetic factors, include proximal inflammatory conditions, like Crohns disease, and systemic illnesses, both metabolic and autoimmune. One of the means by which this equilibrium is achieved is through induction of both effector and suppressor or regulatory arms of the adaptive immune system. In mice, Helicobacter species induce regulatory (iTreg) and follicular helper (Tfh) T cells in the colon-draining mesenteric lymph nodes under homeostatic conditions, but can instead induce inflammatory Th17 cells when iTreg cells are compromised3, 4. How Helicobacter hepaticus and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here, we investigated which cells and molecular components are required to convey the microbial instruction for the iTreg differentiation program. We found that antigen presentation by cells expressing ROR{gamma}t, rather than by classical dendritic cells, was both required and sufficient for iTreg induction. These ROR{gamma}t+ cells, likely to be type 3 innate lymphoid cells (ILC3) and/or a recently-described population of Aire+ cells termed Janus cells5, require the MHC class II antigen presentation machinery, the chemokine receptor CCR7, and v integrin, which activates TGF-{beta}, for iTreg cell differentiation. In the absence of any of these, instead of iTreg cells there was expansion of microbiota-specific pathogenic Th17 cells, which were induced by other antigen presenting cells (APCs) that did not require CCR7. Thus, intestinal commensal microbes and their products target multiple APCs with pre-determined features suited to directing appropriate T cell differentiation programs, rather than a common APC that they endow with appropriate functions. Our results illustrate the ability of microbiota to exploit specialized functions of distinct innate immune system cells, targeting them to achieve the desired composition of equipoised T cells, thus maintaining tolerance.

immunology↗

bioRxiv2020

Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes

Differentiation of intestinal T helper 17 (Th17) cells, which contribute to mucosal barrier protection from invasive pathogens, is dependent on colonization with distinct commensal bacteria. Segmented filamentous bacteria (SFB) are sufficient to support Th17 cell differentiation in mouse, but the molecular and cellular requirements for this process remain incompletely characterized. Here we show that intestine-draining mesenteric lymph nodes (MLN) are the dominant site of SFB-induced intestinal Th17 cell differentiation. Subsequent migration of these cells to the intestinal lamina propria is dependent on their up-regulation of integrin {beta}7. Stat3-dependent induction of ROR{gamma}t, the Th17 cell-specifying transcription factor, largely depends on IL-6, but signaling through the receptors for IL-21 and IL-23 can compensate for absence of IL-6 to promote SFB-directed Th17 cell differentiation. These results indicate that redundant cytokine signals guide commensal microbe-dependent Th17 cell differentiation in the MLN and accumulation of the cells in the lamina propria.

immunology↗