Beilin, C.; (2011) Common cytokine receptor γ chain deficiency in dendritic cells: implications for immunity. Doctoral thesis, UCL (University College London).
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X-linked Severe Combined Immunodeficiency (X-SCID) caused by mutations in the common cytokine receptor γ chain (γc) is a fatal disease in which the immune system is severely compromised as T and NK cells are absent or profoundly diminished. Although dendritic cells (DCs) are key antigen presenting cells and are crucial for the induction of normal immune responses, little is known about their function in this disease. This is of specific importance as the myeloid compartment, including DCs, frequently remains of host origin, and therefore γc-deficient, after bone marrow transplant or gene therapy for this form of SCID. Curiously, even after curative treatment, patients with X-SCID continue to have a long-term susceptibility to human papilloma virus infection. We hypothesised that this could be due to persistent myeloid defects. Using a murine model of X-SCID, we demonstrated that, in the absence of functional γc, DCs are less efficient at priming antigen-specific responses in γc-expressing CD4+ T cells. Despite the widely held view that IL-15Rα is the chain responsible for IL-15 transpresentation to NK and CD8+ T cells, here we have shown that expression of the γc by DCs is necessary for effective transpresentation to CD4+ T cells. In a novel system of supported planar bilayers mimicking the T cell interface, we demonstrated that DC-expressed γc colocalises with MHC II clusters and mediates IL-15Rα recruitment to the immunological synapse (IS). This depended on simultaneous TCR engagement with MHC-bound antigen, suggesting that IL-15 transpresentation may have important costimulatory function for T cell activation. Altogether, these data indicate that γc-deficiency impairs DC functions and reveal a novel mechanism for recruitment or stabilization of DC IL-15/IL-15Rα complexes at the IS leading to localized transpresentation of IL-15. The contribution of myeloid γc-deficiency to persistent immunodeficiency in transplanted X-SCID patients warrants further investigation.
|Title:||Common cytokine receptor γ chain deficiency in dendritic cells: implications for immunity|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Infection and Immunity > ICH - Molecular Immunology Unit|
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