Improving the outcome of children with congenital athymia. (360G-Wellcome-222096_Z_20_Z)

Congenital athymia causes life-threatening T-cell immunodeficiency. The only definitive treatment is thymus transplantation (TT). Despite lack of major histocompatibility complex (MHC)-matching between donor and host, transplanted thymus, repopulated by recipient bone marrow-derived lymphoid progenitors, supports functional T-cell development restricted to host MHC alleles. Though lifesaving, TT results in subnormal circulating T-cell numbers and frequent autoimmune complications. I aim to dissect the cellular and molecular mechanisms of lympho-stromal crosstalk and thymopoiesis in the context of MHC- mismatched TT by using single-cell and spatial genomics on pre-transplantation cultured thymic tissue and post-transplantation graft biopsies. Donor thymocytes, possibly including long-lasting lymphoid progenitors, remaining at the time of transplantation despite lympho-depleting preparatory culture, may contribute to this crosstalk and assist thymic epithelial cell (TEC) homeostasis. Other recipient-derived haematopoietic cells may migrate into the graft to replace direct interactions between developing host thymocytes and TECs. Alternatively host TECs may develop in the transplanted thymus. I hypothesise that partial MHC-matching improves crosstalk signalling, achieving better immunoreconstitution and less autoimmunity. Optimising in vitro differentiation and maturation of TECs derived from pluripotent stem cells will make the in-depth investigation of MHC-TCR interactions and downstream signalling possible. New insights into TEC biology will advance alternative approaches to thymus replacement therapy.