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Adiponectin-expressing Treg facilitate T lymphocyte development in thymic nurse cell complexes.

ABSTRACT: Adiponectin is a well-known insulin sensitizer and anti-inflammatory molecule, possessing therapeutic potentials in cardiovascular, metabolic and cancer diseases. Results of the present study demonstrate that adiponectin is expressed in a population of regulatory T-cells (Treg) resided within the thymic nurse cell (TNC) complexes. Adoptive transfer of adiponectin-expressing Treg precursors effectively attenuated obesity, improved glucose and insulin tolerance, prevented fatty liver injuries in wild-type mice fed a high-fat diet, and significantly inhibited breast cancer development in MMTV-PyVT transgenic mice. Within the TNC complexes, locally produced adiponectin bound to and regulated the expression as well as the distribution of CD100, a transmembrane lymphocyte semaphorin, in turn modulating the lymphoepithelial interactions to facilitate T-cell development and maturation. In summary, adiponectin plays an important role in the selection and development of T lymphocytes within the TNC complexes. Adiponectin-expressing Treg represent a promising candidate for adoptive cell immunotherapy against obesity-related metabolic and cancer diseases.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7966800 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Adiponectin-expressing Treg facilitate T lymphocyte development in thymic nurse cell complexes.

Zhang Yiwei Y Cao Handi H Chen Jie J Li Yuanxin Y Xu Aimin A Wang Yu Y

Communications biology 20210316 1

Adiponectin is a well-known insulin sensitizer and anti-inflammatory molecule, possessing therapeutic potentials in cardiovascular, metabolic and cancer diseases. Results of the present study demonstrate that adiponectin is expressed in a population of regulatory T-cells (Treg) resided within the thymic nurse cell (TNC) complexes. Adoptive transfer of adiponectin-expressing Treg precursors effectively attenuated obesity, improved glucose and insulin tolerance, prevented fatty liver injuries in w ...[more]

PMID: 33727658

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Project description:The thymus is involved in autoimmune Myasthenia gravis (MG) associated with anti-acetylcholine (AChR) antibodies. In MG, thymic regulatory T cells (Treg) are not efficiently suppressive, and conventional T cells (Tconv) are resistant to suppression. To better understand the specific role of the thymus in MG, we compared the phenotype and function of peripheral and thymic Treg and Tconv from controls and MG patients. Suppression assays with thymic or peripheral CD4 + T cells showed that the functional impairment in MG was more pronounced in the thymus than in the periphery. Phenotypic analysis of Treg showed a significant reduction of resting and effector Treg in the thymus but not in the periphery of MG patients. CD31, a marker lost with excessive immunoreactivity, was significantly reduced in thymic but not blood resting Treg. These results suggest that an altered thymic environment may explain Treg differences between MG patients and controls. Since thymic epithelial cells (TECs) play a major role in the generation of Treg, we co-cultured healthy thymic CD4 + T cells with control or MG TECs and tested their suppressive function. Co-culture with MG TECs consistently hampers regulatory activity, as compared with control TECs, suggesting that MG TECs contribute to the immune regulation defects of MG CD4 + T cells. MG TECs produced significantly higher thymic stromal lymphopoietin (TSLP) than control TECs, and a neutralizing anti-TSLP antibody partially restored the suppressive capacity of Treg derived from co-cultures with MG TECs, suggesting that TSLP contributed to the defect of thymic Treg in MG patients. Finally, a co-culture of MG CD4 + T cells with control TECs restored numbers and function of MG Treg, demonstrating that a favorable environment could correct the immune regulation defects of T cells in MG. Altogether, our data suggest that the severe defect of thymic Treg is at least partially due to MG TECs that overproduce TSLP. The Treg defects could be corrected by replacing dysfunctional TECs by healthy TECs. These findings highlight the role of the tissue environment on the immune regulation.

Project description:Delayed immune recovery is a characteristic feature of allogeneic hematopoietic stem cell transplantation in adult recipients. Although recipient thymic T-cell neogenesis contributes to T-cell regeneration after transplantation, thymic recovery in the transplant recipient decreases with increasing age, and is diminished by intensive preconditioning regimens and graft-versus-host disease. In adult recipients, most events that determine transplant success or failure occur during the period when the majority of circulating T cells is derived from the donor's post thymic T-cell repertoire. As a result, the make-up of the donor lymphocyte compartment may strongly influence immune recovery and transplant outcomes. The aim of this study was to examine donor lymphocyte counts in a series of patients undergoing an allogeneic hematopoietic stem cell transplant to identify the potential contribution of donor regulatory and conventional T lymphocyte populations to immune recovery and transplant outcomes. We examined donor lymphocyte subset counts in relation to post-transplant lymphocyte recovery and transplant events in 220 consecutive myeloablative, T-cell-depleted, HLA-identical sibling hematopoietic stem cell transplant recipients with hematologic malignancies. In a multivariate analysis, absolute numbers of donor CD4(+) recent thymic emigrants were associated with overall survival (P=0.032). The donors' absolute lymphocyte count and thymic production of regulatory T cells were both associated with extensive chronic graft-versus-host disease (P=0.002 and P=0.022, respectively). In conclusion, these results identify donor immune characteristics that are associated with lymphocyte recovery, extensive chronic graft-versus-host disease, and survival in the recipient following allogeneic hematopoietic stem cell transplantation. The study reported here was performed using peripheral blood samples drawn from donors and patients enrolled in the ClinicalTrials.gov-registered trials NCT00001623, NCT00001873, NCT00353860, NCT00066300, NCT00079391, and NCT00398346.

Dataset Information

Adiponectin-expressing Treg facilitate T lymphocyte development in thymic nurse cell complexes.

Publications

Adiponectin-expressing Treg facilitate T lymphocyte development in thymic nurse cell complexes.

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