Blockade of TGF-beta signaling in T cells prevents the development of experimental glomerulonephritis.
Anti-glomerular basement membrane (GBM) Ab-induced glomerulonephritis (GN) at late stage is thought to be mediated by T cells. However, signaling pathways of T cells that are involved in the development of anti-GBM Ab-induced GN are unclear. We have recently established transgenic mice expressing Smad7, an inhibitor of TGF-beta signaling, in mature T cells, where signaling by TGF-beta was blocked specifically in T cells. In this study, we showed that anti-GBM Ab-induced GN was suppressed in several measures in the transgenic mice including the severity of glomerular changes, proteinuria, renal function, and CD4 T cell infiltration into the glomeruli without down-regulation of CD62 ligand (CD62L) (L-selectin) expression on CD4 T cells. Furthermore, treatment with the soluble fusion protein of CD62L and IgG enhanced anti-GBM Ab-induced GN. These findings indicated that blockade of TGF-beta signaling in T cells prevented the development of anti-GBM Ab-induced GN. Because CD62L on T cells appears to be inhibitory for the development of anti-GBM Ab-induced GN, persistent expression of CD62L on CD4 T cells may explain, at least in part, the suppression of anti-GBM Ab-induced GN in the transgenic mice. Our findings suggest that the development of anti-GBM Ab-induced GN requires TGF-beta/Smad signaling in T cells.
Kanamaru
Y
Y
Allergy Research Center, Division of Nephrology Juntendo University School of Medicine, Tokyo, Japan.
Nakao
A
A
Mamura
M
M
Suzuki
Y
Y
Shirato
I
I
Okumura
K
K
Tomino
Y
Y
Ra
C
C
D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000633:toxicity; D001323:Autoantibodies / Q000378:metabolism / Q000633:toxicity; D001485:Basement Membrane / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003176:Complement C3 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007275:Injections, Intravenous; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019041:L-Selectin / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051906:Smad7 Protein; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology*
D000906:Antibodies; D001323:Autoantibodies; D003176:Complement C3; D004268:DNA-Binding Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C051951:antiglomerular basement membrane antibody; D019041:L-Selectin