Polysialic acid governs T-cell development by regulating progenitor access to the thymus

Abstract

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 contactdependent 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.bone marrow niche ͉ hematopoiesis ͉ mobilization ͉ development

Sequences from the First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Allow O-Glycan Polysialylation of an Adhesion Molecule Chimera

“…In addition, polysialic acid has been demonstrated to be involved in hematopoietic development (26,27). For example, ST8SiaIV Ϫ/Ϫ mice have reduced thymocyte numbers due to fewer progenitor cells mobilizing to the thymus (27).…”

“…Recently, polysialylated NCAM has been shown to enhance metastasis of a murine model of lung cancer (24) and has been implicated in colorectal carcinoma progression (25). In addition, polysialic acid has been demonstrated to be involved in hematopoietic development (26,27). For example, ST8SiaIV Ϫ/Ϫ mice have reduced thymocyte numbers due to fewer progenitor cells mobilizing to the thymus (27).…”

The Expression Profile of De-N-acetyl Polysialic Acid (NeuPSA) in Normal and Diseased Human Tissue

“…Polysialylated neural cell adhesion molecule (PSA-NCAM), by far the most abundant polysialylated protein, is highly expressed in cells derived from all germ layers during fetal development but is limited in adult tissues (2). For example, PSA-NCAM is expressed in regenerating areas of the adult brain such as the olfactory bulb and hippocampus (2,3) and also in leukocytes (4), but most other tissues are thought to contain little PSA. In addition to NCAM, synaptic cell adhesion molecule 1 (5), the ␣ subunit of the voltage-sensitive sodium channel (6), the integrin ␣5 subunit (7), the scavenger receptor CD36 (8), neuropilin-2 (9), and the polysialyltransferases that produce PSA, ST8SiaII, and ST8SiaIV, also known as STX and PST, respectively (10), are also modified with PSA.…”

“…polysialic acid (PSA) 4 ) in human tissues is developmentally regulated (1). Polysialylated neural cell adhesion molecule (PSA-NCAM), by far the most abundant polysialylated protein, is highly expressed in cells derived from all germ layers during fetal development but is limited in adult tissues (2).…”

PolySia-Specific Retargeting of Oncolytic Viruses Triggers Tumor-Specific Immune Responses and Facilitates Therapy of Disseminated Lung Cancer

“…Furthermore, the high degree of tumor selectivity promises a lower risk for offtarget infection. It has been shown that T-cell progenitors transiently express polySia (38). However, lymphatic cells are resistant to adenoviral infection due to the lack of integrins.…”