IntroductionMesenchymal stem cell (MSC) developmental plasticity has generated remarkable interest in their potential use in cell-based tissue engineering and regeneration. 1 MSCs were also observed to have profound immunomodulatory effects. 2 As a result, researchers are evaluating their clinical use in an expanding array of common immune-mediated diseases, including type 1 diabetes mellitus, graft-versus-host disease, collagen-induced arthritis, and multiple sclerosis. [3][4][5] To date, more than 120 clinical trials have been initiated using MSCs, at a pace faster than any other cell therapy (www.clinicaltrials.org).Given the potential for expansion of MSCs from a single donor followed by subsequent use in patients, there has been growing interest in the use of allogeneic MSCs. 2 An understanding of MSC survival, as well as of the mechanisms by which these cells evade cytotoxic immune responses, is paramount for tailoring such MSC-based strategies. MSCs lack expression of major histocompatibility complex (MHC) class II and classic positive costimulatory molecules. As a result, MSCs historically were regarded as hypoimmunogenic cells. 6 Indeed, MSCs cultured with T cells do not cause T-cell proliferation, fail to induce interferon-␥ and tumor necrosis factor-␣ production in human CD8 ϩ cytotoxic T-cell (CTL) clones, and trigger weaker up-regulation of CD25 on CTLs. 7,8 MSCs were also shown to be capable of down-regulating CTL-mediated lysis. 9 Indeed, after exposure of MSCs to primed CTLs in a mixed lymphocyte reaction, donor T cells but not donor MSCs were lysed by the CTLs in cocultures. 9 Rasmusson et al 7 have shown that MSCs are also resistant to lysis by fully differentiated effector CTLs.However, recent studies suggest that MSCs are not as immunoprivileged as once thought. 10 MSCs were found to up-regulate the expression of MHC class II and costimulatory molecules in an inflammatory milieu, and they are indeed recognized by the host immune system, which results in their rejection, albeit with delay. 11 The partial immunogenicity of MSCs suggests that these cells possess tools by which they, in part, evade host immune responses.The therapeutic success of using MSCs across MHC barriers is not only dependent on their failure to induce activation of CD4 and CD8 T-cell responses but also on their escape from the granzyme B (GrB) lytic activity of CTLs. 12,13 GrB is a major constituent of CTL/natural killer cell granules, binds mannose-6-phosphate receptor, and induces killing of target cells via activation of caspases and the promotion of mitochondrial permeabilization. 14-17 GrB activity is, in turn, tightly regulated through its interaction with peptidase inhibitors that belong to the serine protease inhibitor (serpin) superfamily. 18,19 Endogenous serpins have been characterized in both mice and humans that specifically inactivate GrB in an irreversible manner and, when overexpressed, allow cells to evade GrB-mediated cytotoxicity. 18,20 Serpins that inhibit GrB are expressed in the cytoplasm and nuclei o...