Endogenous Matrix Metalloproteinases 2 and 9 Regulate Activation of CD4⁺and CD8⁺T cells

Abstract

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.

IL-22 Is Mainly Produced by IFNγ-Secreting Cells but Is Dispensable for Host Protection against Mycobacterium tuberculosis Infection

“…In the present study, the differential analysis of naive, effector memory and central memory T cells also revealed that IL-22 has no general influence on the development of memory and central memory T cells after infection with Mtb . Reduced numbers of naive CD4 + T cells at early stages of infection day may be explained by slightly reduced expression of the IL-22-dependent chemokines MMP-1 and CXCL-10 in IL-22 −/− mice, which are involved in activation and recruitment of T cells [56], [57], [70], [71] (data not shown). In line with the rather unaffected development of memory and central memory T cells in Mtb -infected IL-22 −/− mice the differentiation of IFNγ + IL-17A + T cells as well as of TH1 and TH17 cells was also fairly induced in the absence of IL-22.…”

Role of sphingolipids in murine radiation‐induced lung injury: protection by sphingosine 1‐phosphate analogs

“…As noted, these include MMP‐9, with increased mRNA levels in the lungs of mice after irradiation, changes that were significantly blunted by fTyS. Because T‐cell activation contributes to the elaboration of radiation pneumonitis (52), an important role for MMP‐9 in the pathogenesis of RILI is suggested by evidence that MMP‐9 regulates lung injury mediated by T cells (53). Separately, similar changes were observed with respect to both S100a8 and S100a9, also known as myeloid‐related proteins 8 and 14 (MRP8 and MRP14), respectively, which are increased in a variety of inflammatory states and contribute to EC barrier disruption and apoptosis (54).…”

Matrix metalloproteinases in kidney homeostasis and diseases

“…After chemotaxis, MMPs also regulate inflammatory cell function. Gelatinase inhibition depresses lymphocyte proliferation in vitro and in vivo in experimental lung disease (12). MMP-8 and -9 promote neutrophil survival (23,58).…”