Elucidation of the mechanism(s) required by CD8{u207A} T lymphocytes for control of different viral infections

Abstract

CD8{u207A} Cytotoxic T lymphocytes (CTLs) are efficient in controlling virus infection because they are equipped with multiple effector mechanisms capable of either inducing cell death or an antiviral state within infected cells. These effector molecules include perforin (Prf), granzymes (Gzms) and gamma-interferon (IFN-{u03B3}). Through the use of gene knockout animals in various viral models, it is now well established that a deficit in any of these effector functions can result in a loss of virus control. However, these effector molecules are not exclusive to CTLs and other effector cells also utilize them, therefore it remains unclear if these effector mechanisms are actually required by CTLs to control virus infections.

I employed 2 models of adoptive transfer of OT-I transgenic CTLs, specific for the ovalbumin (OVA)-derived peptide SIINFEKL and deficient in one or more effector molecule(s), combined with infection with various recombinant viruses expressing this peptide to identify the effector molecule(s) necessary for primary or memory CTLs in mediating antiviral activity against two closely related orthopoxviruses: ectromelia virus (ECTV-OVA), vaccinia virus (VACV-OVA). The adoptive transfer model was also used to investigate whether similar antiviral effector molecule(s) are required by primary CTLs to control other viruses such as herpes simplex virus type 1 (HSV-1-OVA) and influenza A virus (IAV-OVA).

Our results show that the effector molecules required for antiviral functions of primary and memory CTLs directed towards two very closely related viruses, ECTV and VACV, are distinct. Prf is required by primary CTLs to control ECTV but not VACV, while IFN-{u03B3} is critical for VACV control but not ECTV. Although Gzm-deficient mice show increased susceptibility to ECTV, neither GzmA nor GzmB are necessary for CTLs to curb either ECTV or VACV replication. There are subtle differences in the degree of dependence on effector functions between primary and memory CTLs in the control of ECTV, as the loss of Prf only partially reduced the ability of memory CTL to control ECTV infection. We have also defined the effector functions required by primary CTLs for the control of HSV-1 and IAV infections and showed CTLs utilize distinctive mechanisms for the control of these other viruses.