Characterization of adiponectin-expressing cells in thymus

Abstract

Thymus is a major organ for T-cells development and maturation to produce multiple distinct subsets of T cells. The lymphoid progenitors migrate from the bone marrow into the circulation and then enter the thymus, where they expand by forming the double negative (DN), double positive (DP) and single positive (SP) T-cells. Adiponectin is a well-known insulin sensitizer and anti-inflammatory molecule, with therapeutic potentials in obesity-related cardiovascular, metabolic and cancer diseases. The present study demonstrated that a population of adiponectin-expressing Treg precursors exists in the thymus. After tail vein injection, these cells rapidly resided within thymus and differentiated into thymic Treg cells (tTreg). Treg cells maintain the immune homeostasis by facilitating self-tolerance, thus preventing autoimmune as well as chronic inflammatory diseases. Treg-based therapy is considered as a promising approach to treat a wide range of inflammatory disorders including atherosclerosis, obesity, insulin resistance and cancer. However, Treg cells are highly heterogeneous. The optimal application of Treg cells relies on our further understanding of the origin, specificity and function of different subsets. In thymus, adiponectin-expressing thymocytes mainly reside in the thymic nurse cell complexes (TNCs) to facilitate the selection and development of T-cells. Adiponectin deficiency not only caused the reduction of TNCs number, also impaired TNCs function, which led to the dysfunctional development of T-cells in thymus. As a consequence, mature CD3+CD4+ T-lymphocytes decreased and the immature CD4+CD8+ lymphocytes accumulated in peripheral blood. The latter promoted tumor development in NOD/SCID mice xenografted with human breast cancer MDA-MB-231 cells. Importantly, adoptive transfer of adiponectin-expressing thymocytes significantly inhibited breast cancer development and lung metastasis in MMTV-PyVT transgenic mice. Moreover, after adoptive transfer, adiponectin-expressing thymocytes were found to enter TNCs and optimize their function, thus preventing the excessive accumulation and release of immature CD4+CD8+ lymphocytes in the circulation, enhancing the T-cell homeostasis in peripheral blood and changing repertoire of tumor-infiltrating Treg cells, which made contributions to preventing tumor promotion. Adiponectin-expressing thymocytes show potential value for adoptive cell immunotherapy against cancer diseases in the future.