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Introduction
Individuals with Down syndrome (DS) have increased susceptibility to infections, particularly respiratory tract infections, with pneumonia being one of the major causes of early death. 1 They are also highly susceptible to viral hepatitis and are more likely to develop certain autoimmune disorders, notably thyroiditis, coeliac disease and Type I diabetes. 2 3 Thus, the immune phenotype in DS is a combination of immunodeficiency and immune dysregulation. The precise cause of immune dysfunction in DS remains unclear, but defective T cell development in the thymus is one contributor. 3-5
Mainstream [alpha][beta] T cell development occurs within the thymus where bone marrow (BM)-derived T cell precursors undergo a complex programme of maturation and differentiation via interactions with specialised resident cells called thymic epithelial cells (TECs). 6 The thymic stromal microenvironment consists predominantly of TECs with contributions from fibroblasts, endothelium and haemopoietically derived conventional dendritic cells (cDC) and can be broadly classified into distinct cortical and medullary compartments. 7 8 Early T cell progenitors (CD4 - CD8- ) enter the thymus at the cortico-medullary junction and migrate through the cortex where they upregulate both CD4 and CD8 expression before the progenitors become restricted to a single CD4 or CD8 lineage. Subsequent migration to medullary regions imposes further selection and developmental events before mature non-self-reactive T cells are exported to the periphery. Thymic stroma cells, such as cortical and medullary epithelial cells (cTEC and mTEC, respectively) regulate thymocyte development by orchestrating functional T cell receptor selection as well as deletion of potential self-reactive clones (reviewed in ref. 6 ). A bidirectional interplay also exists, in which interactions between thymocytes and stromal elements reciprocally regulate the organisation and development of the thymic microenvironment. 9-13
Morphologically, the DS thymus is typically small and exhibits cortical atrophy, a loss of cortico-medullary demarcation 5 and lymphopenia due to a defect in the development of thymocytes. 3 In the thymus, there are reduced numbers of phenotypically mature T cells that express high levels of the [alpha][beta]TCR-CD3 complex 14 and in the periphery, absolute numbers of CD4 T helper cells and CD8 cytotoxic T cells are reduced. 4 Functionally, T lymphocytes isolated from individuals with DS exhibit reduced proliferation upon stimulation 3 15 16 and cytokine production is defective; the consensus...