Recruitment of adult thymic progenitors is regulated by lymphotoxin beta receptor (HEM4P.240)

Abstract

Abstract Continuous homing of hematopoietic progenitors from peripheral blood to thymus is essential for the functional maintenance of thymus, especially upon thymic injury. Here we identified the signaling of lymphotoxin beta receptor (LTβR), is essential for the thymic progenitor settling. Dramatically reduced frequency and number of early T-lineage progenitors (ETP) were found in the steady thymus of LTβR knockout (KO) mice. This is probably not due to impaired development of hematopoietic progenitors, since normal frequencies of T-cell precursor were found in the bone marrow of LTβR KO mice. Further experiment by tracing adoptively transferred bone marrow cells directly confirmed a thymic homing defect in LTβR KO mice. Progenitor thymic settling is mediated by a cascade of adhesion and signal events, which involves P-selectin, CCL25, VCAM-1/ICAM-1, etc. We identified P-selectin is down-regulated in the thymi of LTβR KO mice while the expression levels of CCL25, VCAM-1, VCAM-1 are normal. Data from bone marrow chimeric mice suggest that LTβR on radio-resistant, likely stromal cells, regulates thymic progenitor receptivity. Finally, LTβR KO mice demonstrated severely impaired thymus regeneration upon thymus-targeted injury. Taken together, our data reveal a novel role of LTβR on the regulation of thymic progenitor homing. Manipulation of this signaling pathway may boost thymic regeneration and immune reconstitution during chemotherapy, radiotherapy or AIDS HAART therapy.