Endogenous matrix metalloproteinases 2 and 9 regulate activation of CD4+ and CD8+ T cells.
We reported that inhibiting matrix metalloproteinases (MMP), known to remodel the extracellular matrix, also down-regulated antigen-specific T-cell responses. However, the direct role of MMP2 and MMP9 in regulating intracellular function in T cells is unknown. Markers of cellular activation and cytokine profiles were examined in anti-CD3-stimulated wild-type C57BL/6 mouse-derived CD4(+) or CD8(+) T cells, or MMP2- or MMP9-deficient (-/-) mice. MMP-sufficient T cells were also treated with SB-3CT, a highly selective inhibitor of MMP2 and MMP9. The effect of MMP-specific inhibition on T cell-dependent, antigen-specific murine lung injury was examined in vivo. SB-3CT induced dose-dependent reductions in anti-CD3-stimulated T-cell proliferation. Although MMP2(-/-) cells were reduced 20%, anti-CD3-induced proliferation was down-regulated 80-85% in MMP9(-/-) or in SB-3CT-treated wild-type CD4(+) and CD8(+) T cells. Intracellular calcium flux was augmented in response to MMP inhibition or deficiency in the same cells, and IL-2 production was reduced in CD4(+) and CD8(+) MMP9(-/-) T cells. SB-3CT-mediated MMP2 and MMP9 inhibition abrogated antigen-specific CD8(+) T cell-mediated lung injury in vivo. MMPs, particularly MMP9, may function intracellularly to regulate T-cell activation. T cell-targeted MMP inhibition may provide a novel approach of immune regulation in the treatment of T cell-mediated diseases.
Benson
Heather L
HL
Department of Biochemistry, Indiana University School of Medicine, Indianapolis, 46202, USA.
Mobashery
Shahriar
S
Chang
Mayland
M
Kheradmand
Farrah
F
Hong
Jeong Soo
JS
Smith
Gerald N
GN
Shilling
Rebecca A
RA
Wilkes
David S
DS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008168:Lung / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D018800:Thy-1 Antigens / Q000378:metabolism
D007166:Immunosuppressive Agents; D018800:Thy-1 Antigens; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D002118:Calcium