Balancing Immune Protection and Immune Pathology by CD8(+) T-Cell Responses to Influenza Infection

Abstract

Influenza A virus (IAV) is a significant human pathogen causing annual epidemics and periodic pandemics. CD8(+) cytotoxic T lymphocyte (CTL)-mediated immunity contributes to the clearance of virus-infected cells, and CTL immunity targeting the conserved internal proteins of IAVs is a key protection mechanism when neutralizing antibodies are absent during heterosubtypic IAV infection. However, CTL infiltration into the airways, its cytotoxicity, and the effects of produced proinflammatory cytokines can cause severe lung tissue injury, thereby contributing to immunopathology. Studies have discovered complicated and exquisite stimulatory and inhibitory mechanisms that regulate CTL magnitude and effector activities during IAV infection. Here, we review the state of knowledge on the roles of IAV-specific CTLs in immune protection and immunopathology during IAV infection in animal models, highlighting the key findings of various requirements and constraints regulating the balance of immune protection and pathology involved in CTL immunity. We also discuss the evidence of cross-reactive CTL immunity as a positive correlate of cross-subtype protection during secondary IAV infection in both animal and human studies. We argue that the effects of CTL immunity on protection and immunopathology depend on multiple layers of host and viral factors, including complex host mechanisms to regulate CTL magnitude and effector activity, the pathogenic nature of the IAV, the innate response milieu, and the host historical immune context of influenza infection. Future efforts are needed to further understand these key host and viral factors, especially to differentiate those that constrain optimally effective CTL antiviral immunity from those necessary to restrain CTL-mediated non-specific immunopathology in the various contexts of IAV infection, in order to develop better vaccination and therapeutic strategies for modifying protective CTL immunity.

Keywords: CD8+ T cells; human; immune regulation; immunopathology; influenza; vaccination.

Figure 1

Regulation of CTL magnitude and effector activity. Right: CTL effector mechanisms against IAV in the infected lung or airway: the IAV-specific CTL targets IAV-infected airway epithelial cells by recognizing a viral peptide presented by MHCI molecules on the surface of infected cells; the CTL then induces cell death in the targeted cell through perforin/granzyme, FasL/Fas, and/or TRAIL/TRAIL-DR signaling; CTLs also can produce IFN-γ, TNF-α, IL-2, CCL3, CCL4, and other cytokines and chemokines to further enhance inflammation and immune activation in the infected lung. Left: various regulatory mechanisms to control the magnitude or effector activity of CTLs though costimulatory (upper) or coinhibitory (lower) signals provided in the lung-draining LNs or the infected lung. An optimal magnitude of protective CTL responses is achieved by balancing the costimulatory and coinhibitory signals, and dysregulation or imbalance among those signals can result in insufficient or exuberant CTL responses, leading to inefficient viral control or damaging immunopathology.