== LAK cell infiltration of lung metastases with high and low content of extracellular matrix components. Matrix metalloproteinases, Proteases, T lymphocyte, Tumour infiltration == Matrix Metalloproteinases == Matrix metalloproteinases (MMPs) are zinc-dependent enzymes of great importance for extracellular matrix (ECM) degradation and basal membrane (BM) penetration by lymphocytes [1,2]. This review summarizes the current data available regarding the reported repertoire of MMPs, their regulation in cytotoxic lymphocytes, T cells and natural killer (NK) cells as well as their impact on tumour infiltration and immunomodulation. There are at least 25 described MMP members, all encoded by different genes. While there is substantial overlap in the MMP Zylofuramine family with respect to specificity, they can be divided into four subgroups, i.e. interstitial collagenases (MMP-1, -8, -13 and MMP-18), Zylofuramine gelatinases (MMP-2 and MMP-9), stromelysins (MMP-3, -10, -11, -7, -26 and MMP-27) and the membrane type MMPs (MT-MMPs) designated MT1-4 (MMP-14-17), MT5- (MMP-24) and MT6-MMP (MMP-25). The Zylofuramine membrane bound MMPs are attached to the cell surface either through a single pass C-terminal transmembrane domain (as for MT1-, MT2-, MT3-, and MT5-MMP) or a glycosyl phosphatidylinositol (GPI) anchor (MT4- and MT6-MMP). == Matrix Metalloproteinases in Lymphocytes == == Expression and Regulation of MMPs in NK Cells == A variety of MMP members, namely F-TCF MMP-1, -2, -9, -13, MT1-, MT2-, MT3- and MT6-MMP has been described to be expressed in freshly isolated human NK cells [36]. In addition, MMP-3, -7, -10 and -11 have been found to be expressed in rodent NK cells [710]. Detection of the various MMPs in NK cells has mainly been done by mRNA expression analysis, i.e. RT-PCR, while MMP-1, -2, -9, MT1- and MT2-MMP have been verified also on the protein level by gelatine zymography and Western blot [35,7]. Even though many MMPs have been detected in Zylofuramine NK cells, less is known about their regulation. NK cells has been shown to up-regulate their expression of MMP-2 upon cross-linking of the activating receptor 2B4 [11] and the prostaglandin PGE2 enhances NK cell secretion of MMP-1 and MMP-3 and can thereby facilitates their migration through Matrigel filters [9]. The chemokine CXCL12 has further been found to enhance human NK cell invasion into type I collagen, as described to be in an MMP-1-dependent manner [4] and stimulation of human NK cells by the cytokine IL-18 increased their migration through Matrigel as well as their expression of MMP-2, -9 and MT1-MMP [5]. In human NK cells the effect of IL-2 is more difficult to study than in T cells, due to being ubiquous for NK cell culture. Using the IL-2-independent NK cell line YT to study the effects of IL-2 on NK cells we found an early stimulatory effect on MMP-9 secretion, and an enhanced migration through Matrigel. However, prolonged IL-2 stimulation resulted in reduced Matrigel invasion and a significant decrease in the expression of several MMPs. Thus, these in vitro data indicate a down-regulation of MMPs in response to continued cytokine stimulation. This may, in part, explain the reduced tumour infiltration by adoptively transferred NK and CD8+ T cells stimulated with IL-2 for 810 days compared to those stimulated with IL-2 for only 46 days [12]. Similarly, a prolonged culture of mouse T cells in IL-2 demonstrated a decreased anti-tumour activity in vivo [13]. == Expression and Regulation of MMPs in T Cells == To date more is known about MMP regulation in T cells compared to NK cells. However, basically all publications in T cells concern MMP-2 and MMP-9 expression, where the latter is constitutively produced and MMP-2 is generated in response to antigen or cytokine stimulation [1418]. Although, MMP-28, MT2-, MT3- and MT5-MMP have also been found to be expressed in T cell populations of 97% purity, by RT-PCR [19]. It could well be that the repertoire of MMPs in T cells is even larger, but has so far not been clearly reported on. For reference, in B cells, so far MMP-3, MMP-9, MMP-26 and MMP-27 have been reported to be expressed [1921], but also for this lineage of lymphocytes MMPs have not yet been thoroughly studied. To our knowledge expression of MMPs has.