Dataset Information

Phenotypic and Functional Changes of Peripheral Ly6C+ T Regulatory Cells Driven by Conventional Effector T Cells.

ABSTRACT: A relatively high affinity/avidity of T cell receptor (TCR) recognition for self-peptide bound to major histocompatibility complex II (self-pMHC) ligands is a distinctive feature of CD4 T regulatory (Treg) cells, including their development in the thymus and maintenance of their suppressive functions in the periphery. Despite such high self-reactivity, however, all thymic-derived peripheral Treg populations are neither homogenous in their phenotype nor uniformly immune-suppressive in their function under steady state condition. We show here that based on the previously defined heterogeneity in the phenotype of peripheral Treg populations, Ly6C expression on Treg marks a lower degree of activation, proliferation, and differentiation status as well as functional incompetence. We also demonstrate that Ly6C expression on Treg in a steady state is either up- or downregulated depending on relative amounts of tonic TCR signals derived from its contacts with self-ligands. Interestingly, peripheral appearance and maintenance of these Ly6C-expressing Treg cells largely differed in an age-dependent manner, with their proportion being continuously increased from perinatal to young adult period but then being gradually declined with age. The reduction of Ly6C+ Treg in the aged mice was not due to their augmented cell death but rather resulted from downregulation of Ly6C expression. The Ly6C downregulation was accompanied by proliferation of Ly6C+ Treg cells and subsequent change into Ly6C- effector Treg with concomitant restoration of immune-suppressive activity. Importantly, we found that this phenotypic and functional change of Ly6C+ Treg is largely driven by conventional effector T cell population. Collectively, these findings suggest a potential cross-talk between peripheral Treg subsets and effector T cells and provides better understanding for Treg homeostasis and function on maintaining self-tolerance.

SUBMITTER: Lee JY

PROVIDER: S-EPMC5864862 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Phenotypic and Functional Changes of Peripheral Ly6C<sup>+</sup> T Regulatory Cells Driven by Conventional Effector T Cells.

Lee Jun Young JY Kim Juhee J Yi Jaeu J Kim Daeun D Kim Hee-Ok HO Han Daehee D Sprent Jonathan J Lee You Jeong YJ Surh Charles D CD Cho Jae-Ho JH

Frontiers in immunology 20180316

A relatively high affinity/avidity of T cell receptor (TCR) recognition for self-peptide bound to major histocompatibility complex II (self-pMHC) ligands is a distinctive feature of CD4 T regulatory (Treg) cells, including their development in the thymus and maintenance of their suppressive functions in the periphery. Despite such high self-reactivity, however, all thymic-derived peripheral Treg populations are neither homogenous in their phenotype nor uniformly immune-suppressive in their funct ...[more]

PMID: 29616017

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Project description:Regulatory T cells (Tregs) migrate between lymphoid and peripheral tissues for maintaining immune homeostasis. Tissue-specific function and functional heterogeneity of Tregs have been suggested, however, correlation between them and inter-tissue movement remain unknown. We used a contact hypersensitivity model of mice expressing a photoconvertible protein for tracking migratory cells. After marking cells in skin, we purified Tregs exhibiting a different migration pattern [Tregs recruiting to or remaining in the skin and emigrating from the skin to draining lymph nodes (dLNs) within half a day] and examined single-cell gene and protein expression profiles. Correlation and unsupervised clustering analyses revealed that Tregs in both skin and dLNs comprised two subpopulations, one highly expressing Nrp1 with variable CD25, Granzyme B, and/or CTLA-4 expression and another with 3 subsets strongly expressing CD25, Granzyme B, or CTLA-4 together with CD39. Characteristic subsets of Tregs remaining in the skin displayed higher CD25 and CD39 expression and lower Granzyme B and CTLA-4 expression compared with Tregs migrating to the skin. In addition, CCR5 expression in Tregs in skin was positively and negatively correlated with CD39 and Nrp-1 expression, respectively. To assess the predictive value of these data for immunotherapy, we blocked CCR5 signaling and found modest downregulation of CD39 and modest upregulation of Nrp1 expression in skin Tregs. Our data reveal a high functional diversity of Tregs in skin that is strongly related to trafficking behavior, particularly skin retention. Modulation of tissue-specific trafficking and function is a promising clinical strategy against autoimmune, infectious, and neoplastic diseases.Significance statementRegulatory T cells (Tregs) are essential for maintaining immune homeostasis. To reveal tissue-specific immunoinhibitory functions and inter-tissue movement correlation based on Treg functional heterogeneity, we examined single-cell gene and protein expression profiles of Tregs recruited to, remaining in, or emigrating from the contact hypersensitivity-induced inflamed skin. Tregs in skin were composed of several subpopulations; one with high Nrp1 expression and another with 3 subsets strongly expressing CD25, Granzyme B, or CTLA-4 together with CD39. Tregs remaining in skin displayed highCD25, CD39, and CCR5 expression, and CCR5 signaling blockade downregulated CD39. A high Treg functional diversity in skin is strongly related to trafficking behavior. Tissue-specific trafficking and functional modulation are a promising clinical strategy against autoimmune, infectious, and neoplastic diseases.

Project description:ObjectiveDendritic cells (DCs) are key orchestrators of immune function. To date, rheumatoid arthritis (RA) researchers have predominantly focused on a potential pathogenic role for CD1c+ DCs. In contrast, CD141+ DCs and plasmacytoid DCs (pDCs) have not been systematically examined, at least in early RA. In established RA, the role of pDCs is ambiguous and, since disease duration and treatment both impact RA pathophysiology, we examined pDCs, and CD1c+ and CD141+ conventional DCs (cDCs), in early, drug-naïve RA (eRA) patients.MethodsWe analyzed the frequency and phenotype of pDCs, CD1c+, and CD141+ DCs from eRA patients and compared findings with healthy controls. In parallel, we performed transcriptional analysis of >600 immunology-related genes (Nanostring) from peripheral blood pDCs, CD1c+ DCs, B cells, T cells, and monocytes.ResultsAll DC subsets were reduced in eRA (n = 44) compared with healthy controls (n = 30) and, for pDCs, this was most marked in seropositive patients. CD141+ and CD1c+ DCs, but not pDCs, had a comparatively activated phenotype at baseline (increased CD86) and CD1c+ DC frequency inversely associated with disease activity. All DC frequencies remained static 12 months after initiation of immunomodulatory therapy despite a fall in activation markers (e.g., HLA-DR, CD40). There was no association between the whole blood interferon gene signature (IGS) and pDC or CD1c+ DC parameters but an inverse association between CD141+ DC frequency and IGS was noted. Furthermore, IFN-I and IFN-III mRNA transcripts were comparable between eRA pDC and other leukocyte subsets (B cells, CD4+, and CD8+ T cells and monocytes) with no obvious circulating cellular source of IFN-I or IFN-III. Transcriptomic analysis suggested increased pDC and CD1c+ DC proliferation in eRA; pDC differentially expressed genes also suggested enhanced tolerogenic function, whereas for CD1c+ DCs, pro-inflammatory transcripts were upregulated.DiscussionThis is the first detailed examination of DC subsets in eRA peripheral blood. Compared with CD1c+ DCs, pDCs are less activated and may be skewed toward tolerogenic functions. CD141+ DCs may be implicated in RA pathophysiology. Our findings justify further investigation of early RA DC biology.

Dataset Information

Phenotypic and Functional Changes of Peripheral Ly6C+ T Regulatory Cells Driven by Conventional Effector T Cells.

Publications

Phenotypic and Functional Changes of Peripheral Ly6C<sup>+</sup> T Regulatory Cells Driven by Conventional Effector T Cells.

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