Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection.
Natural killer (NK) cells have the potential to deliver both direct antimicrobial effects and regulate adaptive immune responses, but NK cell yields have been reported to vary greatly during different viral infections. Activating receptors, including the Ly49H molecule recognizing mouse cytomegalovirus (MCMV), can stimulate NK cell expansion. To define Ly49H's role in supporting NK cell proliferation and maintenance under conditions of uncontrolled viral infection, experiments were performed in Ly49h(-/-), perforin 1 (Prf1)(-/-), and wild-type (wt) B6 mice. NK cell numbers were similar in uninfected mice, but relative to responses in MCMV-infected wt mice, NK cell yields declined in the absence of Ly49h and increased in the absence of Prf1, with high rates of proliferation and Ly49H expression on nearly all cells. The expansion was abolished in mice deficient for both Ly49h and Prf1 (Ly49h(-/-)Prf1(-/-)), and negative consequences for survival were revealed. The Ly49H-dependent protection mechanism delivered in the absence of Prf1 was a result of interleukin 10 production, by the sustained NK cells, to regulate the magnitude of CD8 T cell responses. Thus, the studies demonstrate a previously unappreciated critical role for activating receptors in keeping NK cells present during viral infection to regulate adaptive immune responses.
Lee
Seung-Hwan
SH
Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA.
Kim
Kwang-Sin
KS
Fodil-Cornu
Nassima
N
Vidal
Silvia M
SM
Biron
Christine A
CA
D000818:Animals; D017252:CD3 Complex / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000494:pharmacology; D007378:Interleukins / Q000502:physiology; D007694:Killer Cells, Natural / Q000502:physiology*; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000502:physiology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000502:physiology*; D000098546:Interleukin-21
D017252:CD3 Complex; D007376:Interleukin-2; D007378:Interleukins; C527096:Klra8 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A; D052899:Pore Forming Cytotoxic Proteins; C510467:perforin 1, mouse; D054353:Perforin; D016753:Interleukin-10; D000098546:Interleukin-21