Polysialic acid governs T-cell development by regulating progenitor access to the thymus.
Although the polysialyltransferase ST8Sia IV is expressed in both primary and secondary human lymphoid organs, its product, polysialic acid (polySia), has been largely overlooked by immunologists. In contrast, polySia expression and function in the nervous system has been well characterized. In this context, polySia modulates cellular adhesion, migration, cytokine response, and contact-dependent differentiation. Provocatively, these same processes are vital components of immune development and function. We previously established that mouse multipotent hematopoietic progenitors use ST8Sia IV to express polySia on their cell surfaces. Here, we demonstrate that, relative to wild-type controls, ST8Sia IV(-/-) mice have a 30% reduction in total thymocytes and a concomitant deficiency in the earliest thymocyte precursors. T-cell progenitors originate in the bone marrow and are mobilized to the blood at regular intervals by unknown signals. We performed in vivo reconstitution experiments in which ST8Sia IV(-/-) progenitors competed with wild-type cells to repopulate depleted or deficient immune subsets. Progenitors lacking polySi exhibited a specific defect in T-cell development because of an inability to access the thymus. This phenotype probably reflects a decreased capacity of the ST8Sia IV(-/-) progenitors to escape from the bone marrow niche. Collectively, these results provide evidence that polySia is involved in hematopoietic development.
Drake
Penelope M
PM
Department of Chemistry, University of California, Berkeley and Howard Hughes Medical Institute, Berkeley, CA 94720-1460, USA.
Stock
Christina M
CM
Nathan
Jay K
JK
Gip
Phung
P
Golden
Kevin P K
KP
Weinhold
Birgit
B
Gerardy-Schahn
Rita
R
Bertozzi
Carolyn R
CR
D000818:Animals; D001681:Biological Assay; D019070:Cell Lineage; D002465:Cell Movement; D048429:Cell Size; D016131:Lymphocyte Subsets / Q000166:cytology; D051379:Mice; D012794:Sialic Acids / Q000378:metabolism*; D012799:Sialyltransferases / Q000172:deficiency / Q000378:metabolism; D055153:Stem Cell Niche / Q000166:cytology / Q000201:enzymology; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology / Q000254:growth & development*; D013997:Time Factors
D012794:Sialic Acids; C021319:polysialic acid; D012799:Sialyltransferases; C525848:ST8SiaIV protein, mouse