Discordant rearrangement of primary and anamnestic CD8+ T cell responses to influenza A viral epitopes upon exposure to bacterial superantigens: Implications for prophylactic vaccination, heterosubtypic immunity and superinfections

Autoři: Courtney E. Meilleur aff001;  Arash Memarnejadian aff001;  Adil N. Shivji aff001;  Jenna M. Benoit aff001;  Stephen W. Tuffs aff001;  Tina S. Mele aff002;  Bhagirath Singh aff001;  Jimmy D. Dikeakos aff001;  David J. Topham aff006;  Hong-Hua Mu aff007;  Jack R. Bennink aff008;  John K. McCormick aff001;  S. M. Mansour Haeryfar aff001
Působiště autorů: Department of Microbiology and Immunology, Western University, London, Ontario, Canada aff001;  Division of General Surgery, Department of Surgery, Western University, London, Ontario, Canada aff002;  Division of Critical Care Medicine, Department of Medicine, Western University, London, Ontario, Canada aff003;  Lawson Health Research Institute, London, Ontario, Canada aff004;  Centre for Human Immunology, Western University, London, Ontario, Canada aff005;  David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America aff006;  Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America aff007;  Viral Immunology Section, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America aff008;  Division of Clinical Immunology & Allergy, Department of Medicine, Western University, London, Ontario, Canada aff009
Vyšlo v časopise: Discordant rearrangement of primary and anamnestic CD8+ T cell responses to influenza A viral epitopes upon exposure to bacterial superantigens: Implications for prophylactic vaccination, heterosubtypic immunity and superinfections. PLoS Pathog 16(5): e32767. doi:10.1371/journal.ppat.1008393
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008393


Infection with (SAg)-producing bacteria may precede or follow infection with or vaccination against influenza A viruses (IAVs). However, how SAgs alter the breadth of IAV-specific CD8+ T cell (TCD8) responses is unknown. Moreover, whether recall responses mediating heterosubtypic immunity to IAVs are manipulated by SAgs remains unexplored. We employed wild-type (WT) and mutant bacterial SAgs, SAg-sufficient/deficient Staphylococcus aureus strains, and WT, mouse-adapted and reassortant IAV strains in multiple in vivo settings to address the above questions. Contrary to the popular view that SAgs delete or anergize T cells, systemic administration of staphylococcal enterotoxin B (SEB) or Mycoplasma arthritidis mitogen before intraperitoneal IAV immunization enlarged the clonal size of ‘select’ IAV-specific TCD8 and reshuffled the hierarchical pattern of primary TCD8 responses. This was mechanistically linked to the TCR Vβ makeup of the impacted clones rather than their immunodominance status. Importantly, SAg-expanded TCD8 retained their IFN-γ production and cognate cytolytic capacities. The enhancing effect of SEB on immunodominant TCD8 was also evident in primary responses to vaccination with heat-inactivated and live attenuated IAV strains administered intramuscularly and intranasally, respectively. Interestingly, in prime-boost immunization settings, the outcome of SEB administration depended strictly upon the time point at which this SAg was introduced. Accordingly, SEB injection before priming raised CD127highKLRG1low memory precursor frequencies and augmented the anamnestic responses of SEB-binding TCD8. By comparison, introducing SEB before boosting diminished recall responses to IAV-derived epitopes drastically and indiscriminately. This was accompanied by lower Ki67 and higher Fas, LAG-3 and PD-1 levels consistent with a pro-apoptotic and/or exhausted phenotype. Therefore, SAgs can have contrasting impacts on anti-IAV immunity depending on the naïve/memory status and the TCR composition of exposed TCD8. Finally, local administration of SEB or infection with SEB-producing S. aureus enhanced pulmonary TCD8 responses to IAV. Our findings have clear implications for superinfections and prophylactic vaccination.

Klíčová slova:

Cloning – Immune response – Influenza A virus – Major histocompatibility complex – Memory recall – Respiratory infections – T cells – Vaccination and immunization


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