TY - JOUR
T1 - Cathepsin C limits acute viral infection independently of NK cell and CD8+ T-cell cytolytic function
AU - Andoniou, Christopher E.
AU - Fleming, Peter
AU - Sutton, Vivien R.
AU - Trapani, Joseph A.
AU - Degli-Esposti, Mariapia A.
PY - 2011/5/1
Y1 - 2011/5/1
N2 - Destruction of target cells by cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells requires the coordinated action of the pore forming protein perforin (Pfp) and the granzyme (Gzm) family of serine proteases. The activation of a number of serine proteases, including GzmA and B, is predominately mediated by cathepsin C (CatC). Deficiencies in CatC-null mice were therefore expected to replicate the defects observed in GzmAB-deficient mice. We have previously determined that GzmAB-deficient mice exhibit increased susceptibility to murine cytomegalovirus (MCMV) infection. Here, we have compared the ability of CatC-/- mice to control MCMV infection with that of GzmAB-deficient animals. We found that CatC-/- mice have organ-specific defects in the ability to control MCMV replication, a phenotype that is distinct to that observed in GzmAB-/- mice. Significantly, the cytolytic function of CatC-deficient NK cells and CTLs elicited during infection was indistinguishable from that of wild-type cells. Hence, CatC is involved in limiting MCMV replication; however, this effect is independent of its role in promoting effector cytolytic activity. These data provide evidence for a novel and unexpected role of CatC during viral infection.
AB - Destruction of target cells by cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells requires the coordinated action of the pore forming protein perforin (Pfp) and the granzyme (Gzm) family of serine proteases. The activation of a number of serine proteases, including GzmA and B, is predominately mediated by cathepsin C (CatC). Deficiencies in CatC-null mice were therefore expected to replicate the defects observed in GzmAB-deficient mice. We have previously determined that GzmAB-deficient mice exhibit increased susceptibility to murine cytomegalovirus (MCMV) infection. Here, we have compared the ability of CatC-/- mice to control MCMV infection with that of GzmAB-deficient animals. We found that CatC-/- mice have organ-specific defects in the ability to control MCMV replication, a phenotype that is distinct to that observed in GzmAB-/- mice. Significantly, the cytolytic function of CatC-deficient NK cells and CTLs elicited during infection was indistinguishable from that of wild-type cells. Hence, CatC is involved in limiting MCMV replication; however, this effect is independent of its role in promoting effector cytolytic activity. These data provide evidence for a novel and unexpected role of CatC during viral infection.
KW - cathepsin c
KW - cytomegalovirus
KW - granzyme
UR - http://www.scopus.com/inward/record.url?scp=79955783700&partnerID=8YFLogxK
U2 - 10.1038/icb.2010.115
DO - 10.1038/icb.2010.115
M3 - Article
C2 - 20975734
AN - SCOPUS:79955783700
SN - 0818-9641
VL - 89
SP - 540
EP - 548
JO - Immunology and Cell Biology
JF - Immunology and Cell Biology
IS - 4
ER -