A T cell-binding fragment of fibrinogen can prevent autoimmunity.
The C-terminal domain of the fibrinogen gamma chain (gammaC) has been shown to bind to the integrins alphaIIbbeta3, alphaMbeta2 and alphaVbeta3. It has also been reported that a peptide derived from the alphaMbeta2-binding site of gammaC can suppress an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Here we have truncated gammaC at position 399 to remove the prothrombotic alphaIIbbeta3-binding site. We show that this truncated version of gammaC, termed gammaC399tr, can bind to activated T cells. In addition, T cells incubated with gammaC399tr 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 gammaC399tr. When administered intraperitoneally, gammaC399tr potently inhibited actively induced EAE and reversed ongoing disease. We hypothesize that the ability of gammaC399tr to inhibit autoreactive immune responses is a result of its ability to bind integrins. This activity was not solely dependent on the alphaMbeta2 integrin-binding site. When polyalanine was substituted for the alphaMbeta2-binding site, the resulting gammaC390polyA 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 gammaC399tr as a novel therapeutic molecule.
Takada
Yoshikazu
Y
Department of Dermatology, University of California Davis School of Medicine, 3301 "C" Street, Suite 1400, Sacramento, CA 95816, USA. ytakada@ucdavis.edu <ytakada@ucdavis.edu>
Ono
Yoko
Y
Saegusa
Jun
J
Sagusa
Jun
J
Mitsiades
Constantine
C
Mitsiades
Nicholas
N
Tsai
Jean
J
He
Yong
Y
Maningding
Ernest
E
Coleman
Annie
A
Ramirez-Maverakis
Dalila
D
Rodrigues
Raphael
R
Rodriquez
Raphael
R
Takada
Yoko
Y
Maverakis
Emanual
E
D000818:Animals; D015551:Autoimmunity / Q000187:drug effects; D001665:Binding Sites; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000517:prevention & control*; D005340:Fibrinogen / Q000737:chemistry* / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D011485:Protein Binding; D013601:T-Lymphocytes / Q000378:metabolism*
D010446:Peptide Fragments; D005340:Fibrinogen