Cathepsin C limits acute viral infection independently of NK cell and CD8+ T-cell cytolytic function.
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.
Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, Western Australia, Australia.
Christopher E
CE
Andoniou
Peter
P
Fleming
Vivien R
VR
Sutton
Joseph A
JA
Trapani
Mariapia A
MA
Degli-Esposti
D000818:Animals; D000941:Antigens / Q000276:immunology; D020789:Cathepsin C / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003586:Cytomegalovirus Infections / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000502:physiology; D009504:Neutrophils / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
D000941:Antigens; D020789:Cathepsin C