Thymus stromal cells

Thymus stromal cells provide chemokines and cytokines during the early stages of T lymphocyte development, and they are essential for promoting the homing thymic-seeding progenitors, inducing T-lineage differentiation, and supporting thymocyte survival and proliferation.^[2] The predominant stromal cells found in the postnatal thymus are thymic epithelial cells (TECs).^[5]

cTECs – (cortical thymic epithelial cells) are located in the cortex, and they are responsible for T lineage commitment and positive selection of early thymocytes,^[5][6] cTECs provide cytokines, such as interleukin 7 (IL-7) and SCF complex, to promote early thymocyte progenitor (ETP) proliferation as well as DLL4-mediated Notch signaling to induce the differentiation of ETP toward the T lineage.^[2]

mTECs (medullary thymic epithelial cells) in the medulla contribute to the development of T cell tolerance by purging autoreactive T lymphocytes by expression of cell-type-specific genes referred to as tissue-restricted antigens (TRA),^[7] and they also participate in the final stages of thymocyte maturation.^[5] mTECs also predominantly express receptor RANK, a major mediator of the thymic crosstalk signal, that is involved in the formation of the thymic medulla.^[1]

Mesenchymal stromal cells are required to create the thymic microenvironment and to maintain epithelial architecture and function in the thymus during organogenesis. They also serve as the major source of retinoic acid, which promotes the proliferation of cTECs. In the adult thymus, mesenchymal cells are found as fibroblastic cells that express a set of structural proteins and functional molecules, such as collagens, CD34, fibroblast-specific protein-1 (FSP1), platelet-derived growth factor receptor α (PDGFRα). They are crucial for the maintenance and regeneration of mTECs.^[1]

Inborn errors of thymic stromal cell development and function lead to impaired T cell development resulting in a susceptibility to opportunistic infections and autoimmunity.^[8] The most serious clinical expression of a thymic stromal cell defect is profound T cell lymphopaenia, presenting as a complete DiGeorge syndrome or severe combined immune deficiency (T⁻B⁺NK⁺ SCID).^[9]

There is large evidence indicating the main target of age-linked thymic dysfunction is thymic stroma with a microenvironment consisting of thymic stromal cells. Studies showed that in the thymic stromal cells, especially cTECs, there is (in the case of an aging thymus) deficiency in the peroxide-quenching enzyme catalase.^[10] This deficiency renders thymic stromal cells sensitive to damage induced by inflammation and damage-associated molecular patterns (DAMPs), such as reactive oxygen species (ROS), and then accumulated metabolic damage and oxidative stress promote thymic dysfunction due to age and accelerated thymus atrophy.^[11]