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A newly identified rare cell subset that drives immune tolerance in dietary and gut microbiota may offer a new therapeutic target, according to researchers.

In the ever-vigilant environment of the gut, immune cells must quickly and precisely decide when to react and when to remain calm. A groundbreaking study published in Nature identified a rare dendritic cell population that plays a pivotal role in this process, promoting tolerance to both dietary and microbiota-derived antigens. These cells, characterized by the co-expression of the transcription factors Prdm16 and RORγt, are now recognized as crucial regulators of peripheral T regulatory (pTreg) cell differentiation.

In their study, author Liuhui Fu, PhD, New York University School of Medicine, and colleagues detailed how Prdm16+ RORγt+ antigen-presenting cells (APCs) are essential to immune education in the gut. When these cells were disrupted in mouse models, tolerance to food and microbiota antigens broke down, leading to inflammation, allergic sensitization, and exaggerated T-helper responses.

“We identified a population of myeloid-derived dendritic cells that co-express Prdm16 and RORγt and are crucial for establishing oral tolerance,” the authors reported.

Unlocking the Identity of Tolerogenic APCs

It has long been known that the regulatory T cell population in the gut relies on antigen-presenting cells for development. However, the specific APCs responsible for promoting pTreg differentiation—especially those involved in responses to food antigens—remained elusive. Earlier hypotheses suggested that classical dendritic cells (cDCs), innate lymphoid cells (ILC3), and various poorly defined RORγt+ cell types might play this role.

By combining conditional gene deletion with single-cell transcriptomics, the research team pinpointed a distinct APC subset defined by high expression of both PRDM16 and RORγt. These cells, now termed tolerogenic dendritic cells (tolDCs), shared a gene expression and chromatin profile with cDCs but were functionally and phenotypically distinct from ILC3s. Mice lacking PRDM16 or RORγt in CD11c+ cells failed to develop microbiota- and food antigen-specific pTregs. Instead, they exhibited increased Th17 and Th2 responses, along with signs of spontaneous type 2 intestinal inflammation, including elevated IgE levels and intestinal hypertrophy.

A Conserved Mechanism With Clinical Potential

Beyond describing these cells, the researchers identified a critical regulatory element—located 7 kb upstream from the RORC transcription start site—required for the development of tolDCs. This enhancer specifically regulates RORγt expression in tolDCs but not in other RORγt+ lineages, such as Th17 or ILC3 cells, suggesting a finely tuned regulatory program susceptible to disruption in disease.

To assess translational relevance, the team turned to human tissue. Single-cell RNA sequencing of mesenteric lymph nodes, tonsils, and intestinal samples revealed a population of human cells co-expressing PRDM16 and RORC, with transcriptomes overlapping those found in mice. Chromatin accessibility patterns were similarly conserved, indicating that tolDCs operate across species and could serve as a viable therapeutic target.

“Our cross-species analysis revealed conserved expression of PRDM16 and RORC in human tissues, supporting an evolutionarily preserved role for tolDC,” the authors wrote.

Functional Consequences of tolDC Loss

Disruption of tolDCs in vivo led to consequences extending beyond the gut. In mouse models of food allergy and allergic asthma, animals lacking functional tolDCs failed to develop tolerance to oral antigens. Despite being pre-fed antigen, these mice mounted strong Th2 responses upon allergen challenge, mirroring the breakdown in tolerance seen in human allergic conditions.

Interestingly, the type of effector T cell response that emerged varied by tissue microenvironment. In the intestine, the absence of tolDCs skewed responses toward Th2 cells, while in other contexts, Th17 or Th1 polarization predominated. This flexibility underscores the central regulatory role these cells play in calibrating immunity.

Looking Ahead: Tolerance as Therapy

As immunologists seek to shift immune responses toward tolerance—whether in allergy, autoimmunity, or organ transplantation—the discovery of tolDCs provides a compelling cellular target. TolDCs’ ability to convert naive T cells into regulatory T cells in the periphery, rather than in the thymus, is particularly relevant to settings where tolerance needs to be re-established or restored.

“Understanding how tolDCs develop and function could lead to strategies that modulate Treg induction in a targeted fashion,” the authors concluded. Genetic variants in PRDM16 have already been associated with asthma, allergic rhinitis, and inflammatory bowel disease, further highlighting the clinical significance of this discovery.

The discovery of tolDCs marks a significant turning point in understanding mucosal immunity, providing new insights into a complex cellular landscape and opening up promising avenues for therapeutic intervention.