title: T cell development critically depends on prethymic stromal patched expression.
abstract: We recently described that T cell specification in mice deficient in the Hedgehog (Hh) receptor Patched (Ptch) is blocked at the level of the common lymphoid progenitor in the bone marrow (BM). Adoptive transfer of wild-type BM in Ptch-deficient mice provides evidence that T cell development strictly depends on Ptch expression in the nonhematopoietic compartment. Transplantation experiments using BM deficient in the glucocorticoid receptor exclude any involvement of the stress hormone corticosterone in our model. Using cell-type-specific knockout mice, we show that T cell development is independent of T cell-intrinsic Ptch expression. Furthermore, Ptch expression by the thymus stroma is dispensable, as revealed by fetal thymus organ culture and thymus transplantation. In contrast, analysis of the earliest thymic progenitors in Ptch-deficient mice indicated that Ptch is required for the development or supply of thymic homing progenitors that give rise to earliest thymic progenitors. Collectively, our findings identified Ptch as an exclusive T cell-extrinsic factor necessary for proper development of T cells at their prethymic stage. This observation may be important for current considerations using Hh inhibitors upstream of Ptch in diseases accompanied by aberrant Hh signaling.
authors.affiliation: Institute of Human Genetics, University of Göttingen, 37073 Göttingen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Uhmann
authors.forename: Jens
authors.initials: J
authors.lastname: van den Brandt
authors.forename: Kai
authors.initials: K
authors.lastname: Dittmann
authors.forename: Ina
authors.initials: I
authors.lastname: Hess
authors.forename: Ralf
authors.initials: R
authors.lastname: Dressel
authors.forename: Claudia
authors.initials: C
authors.lastname: Binder
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.forename: Hans
authors.initials: H
authors.lastname: Christiansen
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.forename: Avinash
authors.initials: A
authors.lastname: Bhandoola
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
authors.forename: Heidi
authors.initials: H
authors.lastname: Hahn
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009924:Organ Culture Techniques; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011828:Radiation Chimera; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
chemical_list: C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface