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.

The immune correlates of protection for an avian influenza H5N1 vaccine in the ferret model using oil-in-water adjuvants

“…Notably, the role for CD8 + T cells in restricting virus replication in the airways, which has only been shown in murine studies (reviewed in refs 16 and 17), was also evident in our study. In addition, high pre-challenge virus-specific IgG antibody titer was associated with improved cellular immunity, as exemplified by ferret 498.…”

“…4C). Because CD8 + T-cells have been associated with rapid viral clearance in murine studies (reviewed in refs 16 and 17), we asked if this was also true in the ferrets. To ensure sufficient data points, we used viral titers in the nasal washes collected on day 5 as a measure of early viral clearance.…”

Contribution of the Purinergic Receptor P2X7 to Development of Lung Immunopathology during Influenza Virus Infection

“…The mechanisms by which the immune response is balanced to achieve influenza virus clearance and tissue repair versus harmful immunopathology are not well understood (5, 6, 33). In this study, we showed that mice lacking the purinergic receptor P2X7 have a better clinical outcome after influenza A virus infection characterized by an increased survival rate with an overall reduced immunopathology of the lungs compared to the wild-type mice.…”

“…Therefore, the response needs to reach a balance to effectively eliminate the invading virus while avoiding the development of immune-mediated pathology of the lungs (1). Although the causes of immunopathology such as excessive production of cytokines and infiltration of inflammatory cells have been reported for influenza virus infection (2, 3), the mechanisms shared by the antiviral host defense required for viral clearance and those required for development of immunopathology are not clearly understood (5, 6). …”

Non-neutralizing antibodies induced by seasonal influenza vaccine prevent, not exacerbate A(H1N1)pdm09 disease

“…The balance between immune protection vs. immunopathology of virus-specific CD8 T cells during influenza virus infection determines the disease outcome43. There is ample evidence showing protection4445464748 mediated by CD8 T cells as well as immunopathology, especially when regulatory mechanisms including costimulatory/inhibitory signals, are altered49505152535455.…”