Residual cytotoxicity and granzyme K expression in granzyme A-deficient cytotoxic lymphocytes

Cytotoxic lymphocytes contain granules that have the ability to induce apoptosis in susceptible target cells, The granule contents include perforin, a pore-forming molecule, and several granzymes, including A and B, which are the most abundant serine proteases in these granules. Granzyme B-deficient cytotoxic T lymphocytes (CTL) have a severe defect in their ability to rapidly induce apoptosis in their targets, but have an intact late cytotoxicity pathway that is in part perforin-dependent, In this report, we have created mice that are deficient for granzyme A acid characterized their phenotype, These mice have normal growth and development and normal lymphocyte development, activation, and proliferation, Granzyme A-deficient CTL have a small but reproducible defect in their ability to induce Cr-51 and I-125-UdR release from susceptible allogeneic target cells. Since other granzyme Alike tryptases could potentially account for the residual cytotoxicity in granzyme A-deficient CTL, we cloned the murine granzyme If,belle, which is linked to granzyme A in humans, and proved that it is also tightly linked with murine granzyme A. The murine granzyme if gene (which encodes a tryptase similar to granzyme A) is expressed at much lower levels than granzyme A in CTL and LAIC cells, but its expression is unaltered in granzyme A-/- mice, The minimal cytotoxic defect in granzyme A-/- CTL could be due to the existence of an intact, functional early killing pathway (granzyme B dependent), or to the persistent expression of additional granzyme tryptases like granzyme K.