CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis
Language: 
English
Abstract: 

CD44 is expressed by a variety of cells, including glial and T cells. Furthermore, in the demyelinating lesions of multiple sclerosis, CD44 expression is chronically elevated. In this study, we demonstrate that targeted deletion of CD44 attenuated myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalitomyelitis (EAE) through novel regulatory mechanisms affecting Th differentiation. Specifically, by developing chimeras and using adoptive transfer experiments, we noted that CD44 deficiency on CD4(+) T cells, but not other cells, conferred protection against EAE induction. CD44 expression played a crucial role in Th differentiation, inasmuch as deletion of CD44 inhibited Th1/Th17 differentiation while simultaneously enhancing Th2/regulatory T cell differentiation. In contrast, expression of CD44 promoted Th1/Th17 differentiation. When osteopontin and hyaluronic acid, the two major ligands of CD44, were tested for their role in Th differentiation, osteopontin, but not hyaluronic acid, promoted Th1/Th17 differentiation. Furthermore, activation of CD44(+) encephalitogenic T cells with myelin oligodendrocyte glycoprotein peptide led to demethylation at the ifnγ/il17a promoter region while displaying hypermethylation at the il4/foxp3 gene promoter. Interestingly, similar activation of CD44-deficient encephalitogenic T cells led to increased hypermethylation of ifnγ/il17a gene and marked demethylation of il4/foxp3 gene promoter. Together, these data suggested that signaling through CD44, in encephalitogenic T cells, plays a crucial role in the differentiation of Th cells through epigenetic regulation, specifically DNA methylation of Th1/Th17 and Th2 cytokine genes. The current study also suggests that molecular targeting of CD44 receptor to promote a switch from Th1/Th17 to Th2/regulatory T cell differentiation may provide a novel treatment modality against EAE.

Author(s): 
Guan, Hongbing
Nagarkatti, Prakash S.
Nagarkatti, Mitzi
Item Type: 
Journal Article
Publication Title: 
Journal of Immunology (Baltimore, Md.: 1950)
Journal Abbreviation: 
J. Immunol.
Publication Date: 
Jun 15, 2011
Publication Year: 
2011
Pages: 
6955-6964
Volume: 
186
Issue: 
12
ISSN: 
1550-6606
DOI: 
10.4049/jimmunol.1004043
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 21551360 PMCID: PMC3650091

Turabian/Chicago Citation

Hongbing Guan, Prakash S. Nagarkatti and Mitzi Nagarkatti. Jun 15, 2011. "CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis." Journal of Immunology (Baltimore, Md.: 1950) 186: 12: 6955-6964. 10.4049/jimmunol.1004043.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.4049/jimmunol.1004043 | issn = 1550-6606 | volume = 186 | pages = 6955-6964 | last = Guan | first = Hongbing | coauthors = Nagarkatti, Prakash S., Nagarkatti, Mitzi | title = CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis | journal = Journal of Immunology (Baltimore, Md.: 1950) | date = Jun 15, 2011 | pmid = | pmc = }} </ref>