Tissue-protective effects of NKG2A in immune-mediated clearance of virus infection.

Kenneth H Ely,Jessica A Ruby,Jun Liu,Mark J Schneider,Mitsuo Matsuoka,Young S Hahn,Richard I Enelow,Yan Wang,Matthew P Deberge,Bumsuk Hahm

doi:10.1371/journal.pone.0108385

Kenneth H Ely, Jessica A Ruby + Show 8 more

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https://doi.org/10.1371/journal.pone.0108385

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Abstract

Virus infection triggers a CD8+ T cell response that aids in virus clearance, but also expresses effector functions that may result in tissue injury. CD8+ T cells express a variety of activating and inhibiting ligands, though regulation of the expression of inhibitory receptors is not well understood. The ligand for the inhibitory receptor, NKG2A, is the non-classical MHC-I molecule Qa1b, which may also serve as a putative restricting element for the T cell receptors of purported regulatory CD8+ T cells. We have previously shown that Qa1b-null mice suffer considerably enhanced immunopathologic lung injury in the context of CD8+ T cell-mediated clearance of influenza infection, as well as evidence in a non-viral system that failure to ligate NKG2A on CD8+ effector T cells may represent an important component of this process. In this report, we examine the requirements for induction of NKG2A expression, and show that NKG2A expression by CD8+ T cells occurs as a result of migration from the MLN to the inflammatory lung environment, irrespective of peripheral antigen recognition. Further, we confirmed that NKG2A is a mediator in limiting immunopathology in virus infection using mice with a targeted deletion of NKG2A, and infecting the mutants with two different viruses, influenza and adenovirus. In neither infection is virus clearance altered. In influenza infection, the enhanced lung injury was associated with increased chemoattractant production, increased infiltration of inflammatory cells, and significantly enhanced alveolar hemorrhage. The primary mechanism of enhanced injury was the loss of negative regulation of CD8+ T cell effector function. A similar effect was observed in the livers of mutant mice infected intravenously with adenovirus. These results demonstrate the immunoregulatory role of CD8+ NKG2A expression in virus infection, which negatively regulates T cell effector functions and contributes to protection of tissue integrity during virus clearance.

Highlights

Acute virus infection results in induction of innate immune responses, which serve to contain replication as well as enhance activation of adaptive responses
We [28] and others [25,32] have shown that CD94/NKG2A engagement on antiviral CD8+ T cells may be associated with dampened effector activity, and we have shown induction of NKG2A expression on antigen specific CD8+ T cell following influenza infection in mice [28]
Migration into infected tissue is required for CD8+ CD94/ NKG2A expression during virus infection

Summary

Introduction

Acute virus infection results in induction of innate immune responses, which serve to contain replication as well as enhance activation of adaptive responses. The cost to the host depends upon multiple factors, in particular the kinetics of virus replication (and antigen load) relative to the kinetics of T cell activation, acquisition of effector activity, and magnitude of the response. The lung is an example of an organ to which considerable injury is unlikely to be compatible with host survival, depending upon the specific components of the respiratory system involved. An overwhelming infection of large airways, coupled with a robust T cell response, would likely result in considerable morbidity (as in the 1957 influenza pandemic), and significant susceptibility to secondary bacterial pneumonia (resulting from multiple potential mechanisms currently under investigation [3,4,5,6,7]). CD8+ T cell effector mechanisms are important contributors to the immunopathology observed in response to virus infection [13,14,15]

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