Influenza infection results in local expansion of memory CD8(+) T cells with antigen non-specific phenotype and function.
Primary viral infections induce activation of CD8(+) T cells responsible for effective resistance. We sought to characterize the nature of the CD8(+) T cell expansion observed after primary viral infection with influenza. Infection of naive mice with different strains of influenza resulted in the rapid expansion of memory CD8(+) T cells exhibiting a unique bystander phenotype with significant up-regulation of natural killer group 2D (NKG2D), but not CD25, on the CD44(high) CD8(+) T cells, suggesting an antigen non-specific phenotype. We further confirmed the non-specificity of this phenotype on ovalbumin-specific (OT-I) CD8(+) T cells, which are not specific to influenza. These non-specific CD8(+) T cells also displayed increased lytic capabilities and were observed primarily in the lung. Thus, influenza infection was shown to induce a rapid, antigen non-specific memory T cell expansion which is restricted to the specific site of inflammation. In contrast, CD8(+) T cells of a similar phenotype could be observed in other organs following administration of systemic agonistic anti-CD40 and interleukin-2 immunotherapy, demonstrating that bystander expansion in multiple sites is possible depending on whether the nature of activation is either acute or systemic. Finally, intranasal blockade of NKG2D resulted in a significant increase in viral replication early during the course of infection, suggesting that NKG2D is a critical mediator of anti-influenza responses prior to the initiation of adaptive immunity. These results characterize further the local bystander expansion of tissue-resident, memory CD8(+) T cells which, due to their early induction, may play an important NKG2D-mediated, antigen non-specific role during the early stages of viral infection.
Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA, USA; Graduate Group in Immunology, University of California, Davis, Davis, CA, USA.
Gail D
GD
Sckisel
Julia K
JK
Tietze
Anthony E
AE
Zamora
Hua-Hui
HH
Hsiao
Stephen O
SO
Priest
Danice E C
DE
Wilkins
Louis L
LL
Lanier
Bruce R
BR
Blazar
Nicole
N
Baumgarth
William J
WJ
Murphy
D000818:Animals; D024201:Bystander Effect / Q000276:immunology*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods; D009980:Influenza A virus / Q000502:physiology*; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
D019013:CD40 Antigens; D007376:Interleukin-2; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K
NKG2D; antigen non-specific; bystander activation; memory CD8; tissue-resident