Dataset Information

T Cell Receptor Is Required for Differentiation, but Not Maintenance, of Intestinal CD4⁺ Intraepithelial Lymphocytes.

ABSTRACT: The gut epithelium is populated by intraepithelial lymphocytes (IELs), a heterogeneous T cell population with cytotoxic and regulatory properties, which can be acquired at the epithelial layer. However, the role of T cell receptor (TCR) in this process remains unclear. Single-cell transcriptomic analyses revealed distinct clonal expansions between cell states, with CD4⁺CD8αα⁺ IELs being one of the least diverse populations. Conditional deletion of TCR on differentiating CD4⁺ T cells or of major histocompatibility complex (MHC) class II on intestinal epithelial cells prevented CD4⁺CD8αα⁺ IEL differentiation. However, TCR ablation on differentiated CD4⁺CD8αα⁺ IELs or long-term cognate antigen withdraw did not affect their maintenance. TCR re-engagement of antigen-specific CD4⁺CD8αα⁺ IELs by Listeria monocytogenes did not alter their state but correlated with reduced bacterial invasion. Thus, local antigen recognition is an essential signal for differentiation of CD4⁺ T cells at the epithelium, yet differentiated IELs are able to preserve an effector program in the absence of TCR signaling.

SUBMITTER: Bilate AM

PROVIDER: S-EPMC7677182 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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T Cell Receptor Is Required for Differentiation, but Not Maintenance, of Intestinal CD4+ Intraepithelial Lymphocytes.

Bilate Angelina M AM London Mariya M Castro Tiago B R TBR Mesin Luka L Bortolatto Juliana J Kongthong Suppawat S Harnagel Audrey A Victora Gabriel D GD Mucida Daniel D

Immunity 20201005 5

The gut epithelium is populated by intraepithelial lymphocytes (IELs), a heterogeneous T cell population with cytotoxic and regulatory properties, which can be acquired at the epithelial layer. However, the role of T cell receptor (TCR) in this process remains unclear. Single-cell transcriptomic analyses revealed distinct clonal expansions between cell states, with CD4+CD8αα+ IELs being one of the least diverse populations. Conditional deletion of TCR on differentiating CD4 ...[more]

PMID: 33022229

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Project description:Recent advances in research suggest that aging has a controllable chronic inflammatory disease aspect. Aging systemic T cells, which secrete pro-inflammatory factors, affect surrounding somatic cells, and accelerate the aging process through chronic inflammation, have attracted attention as potential therapeutic targets in aging. On the other hand, there are few reports on the aging of the intestinal immune system, which differs from the systemic immune system in many ways. In the current study, we investigated the age-related changes in the intestinal immune system, particularly in T cells. The most significant changes were observed in the CD4+ T cells in the small intestinal IEL, with a marked increase in this fraction in old mice and reduced expression of CD27 and CD28, which are characteristic of aging systemic T cells. The proliferative capacity of aging IEL CD4+ T cells was significantly more reduced than that of aging systemic T cells. Transcriptome analysis showed that the expression of inflammatory cytokines was not upregulated, whereas Cd8α, NK receptors, and Granzymes were upregulated in aging IEL CD4+ T cells. Functional analysis showed that aging IEL T cells had a higher cytotoxic function against intestinal tumor organoids in vitro than young IEL T cells. scRNAseq revealed that splenic T cells show a transition from naïve to memory T cells, whereas intestinal T cells show the emergence of a CD8αα+CD4+ T cell fraction in aged mice, which is rarely seen in young cells. Further analysis of the aging IEL CD4+ T cells showed that two unique subsets are increased that are distinct from the systemic CD4+ T cells. Subset 1 has a pro-inflammatory component, with expression of IFNγ and upregulation of NFkB signaling pathways. Subset 2 does not express IFNγ, but upregulates inhibitory molecules and nIEL markers. Expression of granzymes and Cd8a was common to both. These fractions were in opposite positions in the clustering by UMAP and had different TCR repertoires. They may be involved in the suppression of intestinal aging and longevity through anti-tumor immunity, elimination of senescent cells and stressed cells in the aging environment. This finding could be a breakthrough in aging research.

Dataset Information

T Cell Receptor Is Required for Differentiation, but Not Maintenance, of Intestinal CD4⁺ Intraepithelial Lymphocytes.

Publications

T Cell Receptor Is Required for Differentiation, but Not Maintenance, of Intestinal CD4<sup>+</sup> Intraepithelial Lymphocytes.

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