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Gastrointestinal health depends on the tolerance of the adaptive immune system to foreign proteins in food. Paradoxically, however, the immune system also mounts an inflammatory response to attack foreign substances. Although foreign food proteins are presented to CD4+ T cells via MHCII, they usually do not trigger an inflammatory response. This tolerance is attributed to the death and functional inactivation of food antigen-specific T cells. However, the regulatory mechanisms of the normal T cell repertoire related to tolerance in individuals are unclear.
Recently, Marc K. Jenkins team from the University of Minnesota published a paper titled Immune tolerance of food is mediated by layers of CD4+ T cell dysfunction. Articles by . In this study, developed a method to isolate food protein peptide-related polyclonal CD4+ T cells, and used single-cell transcriptome analysis to identify the dominant Treg and Th lin- cells. Th lin- cells can use IL-2 to differentiate into Treg cells to participate in oral tolerance.
The authors studied wheat protein peptide-specific CD4+ T cells to assess the body's normal response to the antigen . The authors identified a peptide from gliadin that binds to MHCII and produced a fluorophore-labeled tetramer that recognizes MHCII containing gliadin. The tetramer was used to study syngeneic T cells in mice and was enriched by magnetic beads for flow cytometric analysis. The authors found that as mice were exposed to a gliadin-containing diet for increasing periods of time, the number of cells enriched in secondary lymphoid organs increased. Among them, 10% are naïve T cells, 60% are Treg cells, 5% are CXCR5+ TFH cells, and few Th1 and Th17 cells express T-bet and RORγt. Approximately 25% of the enriched cells lacked these markers but expressed the T cell anergy markers FR4 and CD73. These cells were termed Th lin- cells by the authors. The authors also fed mice with other foreign peptides or normal feed and proved that Th lin- and Treg cells are the main cell groups that recognize foreign protein peptides. Source analysis found that Th lin- cells mainly originate from the liver and intestine secondary lymphoid organs.
The authors next began to analyze Th lin-cells. Single-cell transcriptome analysis showed that Th lin- is a complex cell mixture that can be divided into five subpopulations , dominated by TFH-like and naïve-like T cells. If treated with cholera toxin, it will increase the proportion of TFH Th1 and Th17 cells and reduce Treg cells, but it will not completely eliminate Th lin- cells. Analysis of the function of Th lin- revealed that Th lin- is an incompetent Treg precursor cell. The analysis found that Th lin- had a lower ability to produce IL-2 than Th1 and Th17. Th lin- was less efficient at generating Th1 than naive T cells after being treated with peptide and poly I:C, and more Th lin- cells and Treg cells were generated. If you block IL-2, you prevent Th lin- cells from turning into Treg cells. Tregs suppress cognate TFH and Th1 production during peptide feeding but are not required for Th lin-cell formation. The authors also explored the immune tolerance function of Treg and Th lin- cells in animal models. The authors found that after mice fed the peptide were treated with poly(I:C), the number of T cells increased 16-fold; while the number of T cells in mice not fed the peptide increased 200-fold. The proportion of Th1 cells in mice after peptide immunization was lower, but Tregs were not significantly higher than those in the untreated group. If Treg cells are deleted, Th1 is significantly increased in peptide-fed mice. These results indicate that Treg and Th lin- cells play an important role in oral tolerance.
Original link:
https://doi.org/10.1038/s41586-022-04916-6
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