Alpha2 beta1 integrin signaling augments T cell receptor-dependent production of interferon-gamma in human T cells.
The mechanisms by which beta1 integrins modulate T cell costimulation are still poorly defined. In this study, we examined the role of collagen-binding integrins alpha1 beta1 and alpha2 beta1 in the regulation of interferon-gamma (IFN-gamma). We demonstrated that ligation of alpha2 beta1 integrin with Collagen type I (Coll I) but not alpha1 beta1 integrin with Collagen IV (Coll IV) significantly augmented T cell receptor (TCR)-dependent expression and production of IFN-gamma by effector T cells. The effect of Coll I was not due to cell adhesion as soluble Coll I also augmented TCR-dependent production of IFN-gamma. Inhibition studies indicated that activation of ERK and JNK MAPKs and PI3K/AKT are necessary for both TCR- and TCR+alpha2 beta1 integrin-dependent IFN-gamma production and that Coll I increases TCR-dependent activation of ERK and JNK MAPKs, and AKT. In addition, our results showed that Coll IV is less potent than Coll I in augmenting TCR-dependent activation of JNK/MAPK, which may explain the differential effect of collagen matrices on TCR-dependent IFN-gamma production. Together, these results indicate that the costimulatory effect of Coll I on IFN-gamma expression is integrated at the levels of ERK and JNK MAPKs and PI3K/AKT signaling pathways and suggest JNK/MAPK as a major signaling pathway of Coll I costimulation. Thus, our study identifies alpha2 beta1 integrin as an important regulatory pathway of IFN-gamma expression and provides novel insights into the signaling mechanisms of integrin costimulation in T cells. As such, this study further supports the functional importance that Coll I interactions may have on the control of T cell-dependent Th1 inflammatory diseases.
Boisvert
Marc
M
Centre de Recherche en Rhumatologie et Immunologie, Faculté de médecine, Université Laval 2705, Blvd. Laurier, local T1-49, Ste-Foy, Québec, G1V 4G2 Canada.
Gendron
Steve
S
Chetoui
Nizar
N
Aoudjit
Fawzi
F
D002448:Cell Adhesion / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D038982:Integrin alpha2beta1 / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*
D038982:Integrin alpha2beta1; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases