A T cell-binding fragment of fibrinogen can prevent autoimmunity

作者:Takada Yoshikazu; Ono Yoko; Sagusa Jun; Mitsiades Constantine; Mitsiades Nicholas; Tsai Jean; He Yong; Maningding Ernest; Coleman Annie; Ramirez Maverakis Dalila; Rodriquez Raphael; Takada Yoko; Maverakis Emanual
来源:Journal of Autoimmunity, 2010, 34(4): 453-459.
DOI:10.1016/j.jaut.2009.11.017

摘要

The C-terminal domain of the fibrinogen gamma chain (gamma C) has been shown to bind to the integrins alpha IIb beta 3, alpha M beta 2 and alpha V beta 3. It has also been reported that a peptide derived from the alpha M beta 2-binding site of gamma C can suppress an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Here we have truncated gamma C at position 399 to remove the prothrombotic alpha IIb beta 3-binding site. We show that this truncated version of gamma C, termed gamma C399tr, can bind to activated T cells. In addition, T cells incubated with gamma C399tr secreted less IFN-gamma when stimulated with antigen and APC; however, cytokine secretion was unaltered when T cells were stimulated non-specifically with a mixture of anti-CD3 and anti-CD28 antibodies. Thus, only antigen-dependent T cell activation is inhibited by gamma C399tr. When administered intraperitoneally, gamma C399tr potently inhibited actively induced EAE and reversed ongoing disease. We hypothesize that the ability of gamma C399tr to inhibit autoreactive immune responses is a result of its ability to bind integrins. This activity was not solely dependent on the alpha M beta 2 integrin-binding site. When polyalanine was substituted for the alpha M beta 2-binding site, the resulting gamma C390polyA was still able to inhibit EAE. To our knowledge, this is the first demonstration that T cells can bind to fibrin (ogen), an important extracellular matrix protein that is deposited at sites of inflammation. Our results also identify gamma C399tr as a novel therapeutic molecule.

  • 出版日期2010-6