Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 182, Issue 4, Pages 1322-1336Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2013.01.003
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Funding
- US Public Health Service [R37-HL28373, RO1-HL51018]
- Reed Foundation
- NIH [T32 GM007223, T32 DK07556]
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Adhesion molecule CD44 is expressed by multiple cell types and is implicated in various cellular and immunological processes. In this study, we examined the effect of global CD44 deficiency on myelin oligodendrocyte glycoprotein peptide (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Compared to C57BL/6 wild-type mice, CD44-deficient mice presented with greater disease severity, increased immune cell numbers in the central nervous system, and increased anti-MUG antibody and proinflammatory cytokine production, especially those associated with T helper 17 (Th17) cells. Further, decreased numbers of peripheral CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) were observed in CD44-knockout mice throughout the disease course. CD44-knockout CD4 T cells exhibited reduced transforming growth factor-beta receptor type I (TGF-beta RI) expression that did not impart a defect in Treg polarization in vitro, but did correlate with enhanced Th17 polarization in vitro. Further, EAE in bone marrow chimeric animals suggested CD44 expression on both circulating and noncirculating cells limited disease severity. Endothelial expression of CD44 Limited T-cell adhesion to and transmigration through murine endothelial. monolayers in vitro. Importantly, we also identified increased permeability of the blood brain barrier in vivo in CD44-deficient mice before and following immunization. These data suggest that CD44 has multiple protective roles in EAE, with effects on cytokine production, T-cell differentiation, T-cell endothelial cell interactions, and blood brain barrier integrity.
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