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 and 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 51Cr and 125I-UdR release from susceptible allogeneic target cells. Since other granzyme A-like tryptases could potentially account for the residual cytotoxicity in granzyme A-deficient CTL, we cloned the murine granzyme K gene, which is linked to granzyme A in humans, and proved that it is also tightly linked with murine granzyme A. The murine granzyme K gene (which encodes a tryptase similar to granzyme A) is expressed at much lower levels than granzyme A in CTL and LAK 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.
Shresta
S
S
Department of Internal Medicine, Washington University School of Medicine, Campus Box 8007, St. Louis, Missouri 63110-1093, USA.
Goda
P
P
Wesselschmidt
R
R
Ley
T J
TJ
D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D053818:Chymases; D003602:Cytotoxicity, Immunologic; D018076:DNA, Complementary / Q000737:chemistry; D005091:Exons; D008040:Genetic Linkage; D053804:Granzymes; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015183:Restriction Mapping; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D053802:Tryptases
D018076:DNA, Complementary; D012333:RNA, Messenger; C509190:Tpsb2 protein, mouse; D053804:Granzymes; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; C509222:Tpsab1 protein, mouse; C509223:Tpsab1 protein, rat; C509221:Tpsb2 protein, rat; D053802:Tryptases; C509212:GZMA protein, human