Natural killer (NK) cell activation depends on the signaling balance of activating and inhibitory receptors. CD94 forms inhibitory receptors with NKG2A and activating receptors with NKG2E or NKG2C. We previously demonstrated that CD94-NKG2 on NK cells and its ligand Qa-1b are important for the resistance of C57BL/6 mice to lethal ectromelia virus (ECTV) infection. We now show that NKG2C or NKG2E deficiency does not increase susceptibility to lethal ECTV infection, but overexpression of Qa-1b in infected cells does. We also demonstrate that Qa-1b is down-regulated in infected and up-regulated in bystander inflammatory monocytes and B cells. Moreover, NK cells activated by ECTV infection kill Qa-1b–deficient cells in vitro and in vivo. Thus, during viral infection, recognition of Qa-1b by activating CD94/NKG2 receptors is not critical. Instead, the levels of Qa-1b expression are down-regulated in infected cells but increased in some bystander immune cells to respectively promote or inhibit their killing by activated NK cells.
Viral infection modulates Qa-1b in infected and bystander cells to properly direct NK cell killing
Disclosures: The authors declare no competing interests exist.
M. Ferez’s present address is Spark Therapeutics, Philadelphia, PA.
A. Lev’s present address is American Association for Cancer Research, Philadelphia, PA.
E.B. Wong’s present address is GlaxoSmithKline, Collegeville, PA.
P. Alves-Peixoto’s present address is Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal, and Life and Health Sciences Research Institute/Research Group in Biomaterials, Biodegradables and Biomimetics-Portugal Government Associate Laboratory, Braga/Guimarães, Portugal.
C. Stotesbury’s present address is GlaxoSmithKline, Collegeville, PA.
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Maria Ferez, Cory J. Knudson, Avital Lev, Eric B. Wong, Pedro Alves-Peixoto, Lingjuan Tang, Colby Stotesbury, Luis J. Sigal; Viral infection modulates Qa-1b in infected and bystander cells to properly direct NK cell killing. J Exp Med 3 May 2021; 218 (5): e20201782. doi: https://doi.org/10.1084/jem.20201782
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