Role of PKR and Type I IFNs in viral control during primary and secondary infection.
Type I interferons (IFNs) are known to mediate viral control, and also promote survival and expansion of virus-specific CD8+ T cells. However, it is unclear whether signaling cascades involved in eliciting these diverse cellular effects are also distinct. One of the best-characterized anti-viral signaling mechanisms of Type I IFNs is mediated by the IFN-inducible dsRNA activated protein kinase, PKR. Here, we have investigated the role of PKR and Type I IFNs in regulating viral clearance and CD8+ T cell response during primary and secondary viral infections. Our studies demonstrate differential requirement for PKR, in viral control versus elicitation of CD8+ T cell responses during primary infection of mice with lymphocytic choriomeningitis virus (LCMV). PKR-deficient mice mounted potent CD8+ T cell responses, but failed to effectively control LCMV. The compromised LCMV control in the absence of PKR was multifactorial, and linked to less effective CD8+ T cell-mediated viral suppression, enhanced viral replication in cells, and lower steady state expression levels of IFN-responsive genes. Moreover, we show that despite normal expansion of memory CD8+ T cells and differentiation into effectors during a secondary response, effective clearance of LCMV but not vaccinia virus required PKR activity in infected cells. In the absence of Type I IFN signaling, secondary effector CD8+ T cells were ineffective in controlling both LCMV and vaccinia virus replication in vivo. These findings provide insight into cellular pathways of Type I IFN actions, and highlight the under-appreciated importance of innate immune mechanisms of viral control during secondary infections, despite the accelerated responses of memory CD8+ T cells. Additionally, the results presented here have furthered our understanding of the immune correlates of anti-viral protective immunity, which have implications in the rational design of vaccines.
Nakayama
Yumi
Y
Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Plisch
Erin H
EH
Sullivan
Jeremy
J
Thomas
Chester
C
Czuprynski
Charles J
CJ
Williams
Bryan R G
BR
Suresh
M
M
D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018398:Homeodomain Proteins / Q000502:physiology; D007156:Immunologic Memory; D007370:Interferon Type I / Q000502:physiology*; D008089:Listeria monocytogenes / Q000502:physiology; D008088:Listeriosis / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology / Q000821:virology; D014615:Vaccinia / Q000276:immunology / Q000473:pathology / Q000821:virology*; D014616:Vaccinia virus / Q000502:physiology; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000502:physiology*
D018398:Homeodomain Proteins; D007370:Interferon Type I; D012333:RNA, Messenger; C064658:RAG-1 protein; D019892:eIF-2 Kinase