Myelin basic protein priming reduces the expression of Foxp3 in T cells via nitric oxide

Saurav Brahmachari, Kalipada Pahan

Research output: Contribution to journalArticlepeer-review

Abstract

Regulatory T cells (Tregs) play a vital role in autoimmune disorders. Among several markers, forkhead box p3 (Foxp3) is the most specific with regard to Treg activity. Therefore, understanding mechanisms that regulate Foxp3 expression is a critical step for unraveling the complicacy of autoimmune pathophysiology. The present study was undertaken to investigate the crosstalk between NO and Tregs. Interestingly, after myelin basic protein (MBP) priming, the expression of Foxp3 decreased in MBP-primed T cells. However, blocking NO either by inhibiting inducible NO synthase with L-N6-(1-iminoethyl)- lysine hydrochloride or through scavenging with PTIO or by pharmacological drugs, such as pravastatin, sodium benzoate, or gemfibrozil, restored the expression of Foxp3 in MBP-primed T cells. However, this restoration of Foxp3 by pharmacological drugs was reversed by S-nitrosoglutathione, an NO donor. Similarly, NO also decreased the populations of Tregs characterized by CD4 +CD25+ and CD25+FoxP3+ phenotypes. We have further confirmed this inverse relationship between NO and Foxp3 by analyzing the mRNA expression of Foxp3 and characterizing CD25+ FoxP3+ or CD4+Foxp3+ phenotypes from inducible NO synthase knockout mice. Moreover, this inverse relation between NO and Foxp3 also was observed during priming with myelin oligodendrocyte glycoprotein, another target neuroantigen in multiple sclerosis, as well as collagen, a target autoantigen in rheumatoid arthritis. Finally, we demonstrate that NO inhibited the expression of Foxp3 in MBP-primed T cells via soluble guanylyl cyclase-mediated production of cGMP. Taken together, our data imply a novel role of NO in suppressing Foxp3+ Tregs via the soluble guanylyl cyclase pathway.

Original languageEnglish (US)
Pages (from-to)1799-1809
Number of pages11
JournalJournal of Immunology
Volume184
Issue number4
DOIs
StatePublished - Feb 15 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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