title: Lymphotoxin β Receptor Controls T Cell Progenitor Entry to the Thymus.
abstract: The recruitment of lymphoid progenitors to the thymus is essential to sustain T cell production throughout life. Importantly, it also limits T lineage regeneration following bone marrow transplantation, and so contributes to the secondary immunodeficiency that is caused by delayed immune reconstitution. Despite this significance, the mechanisms that control thymus colonization are poorly understood. In this study, we show that in both the steady-state and after bone marrow transplant, lymphotoxin β receptor (LTβR) controls entry of T cell progenitors to the thymus. We show that this requirement maps to thymic stroma, further underlining the key importance of this TNFR superfamily member in regulation of thymic microenvironments. Importantly, analysis of the requirement for LTβR in relationship to known regulators of thymus seeding suggests that it acts independently of its regulation of thymus-homing chemokines. Rather, we show that LTβR differentially regulates intrathymic expression of adhesion molecules known to play a role in T cell progenitor entry to the thymus. Finally, Ab-mediated in vivo LTβR stimulation following bone marrow transplant enhances initial thymus recovery and boosts donor-derived T cell numbers, which correlates with increased adhesion molecule expression by thymic stroma. Collectively, we reveal a novel link between LTβR and thymic stromal cells in thymus colonization, and highlight its potential as an immunotherapeutic target to boost T cell reconstitution after transplantation.
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Beth
authors.initials: B
authors.lastname: Lucas
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Kieran D
authors.initials: KD
authors.lastname: James
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Emilie J
authors.initials: EJ
authors.lastname: Cosway
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Parnell
authors.affiliation: Trudeau Institute, Saranac Lake, NY 12983; and.
authors.forename: Alexi V
authors.initials: AV
authors.lastname: Tumanov
authors.affiliation: Infectious and Inflammatory Diseases Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Carl F
authors.identifier: 0000-0002-5006-418X
authors.initials: CF
authors.lastname: Ware
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: William E
authors.initials: WE
authors.lastname: Jenkinson
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; g.anderson@bham.ac.uk.
authors.forename: Graham
authors.identifier: 0000-0002-2917-4085
authors.initials: G
authors.lastname: Anderson
mesh_terms: D000818:Animals; D002465:Cell Movement; D053259:Lymphotoxin beta Receptor / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013234:Stem Cells / Q000166:cytology* / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology
chemical_list: D053259:Lymphotoxin beta Receptor