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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\u2013deficient 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.<\/jats:p>","DOI":"10.1084\/jem.20201782","type":"journal-article","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T13:35:41Z","timestamp":1616679341000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Viral infection modulates Qa-1b in infected and bystander cells to properly direct NK cell killing"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2255-7136","authenticated-orcid":true,"given":"Maria","family":"Ferez","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1229-7732","authenticated-orcid":true,"given":"Cory J.","family":"Knudson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4197-6742","authenticated-orcid":true,"given":"Avital","family":"Lev","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Philadelphia, PA 2"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9018-2589","authenticated-orcid":true,"given":"Eric B.","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6082-6838","authenticated-orcid":true,"given":"Pedro","family":"Alves-Peixoto","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 1"},{"name":"Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal 3"},{"name":"Life and Health Sciences Research Institute\/Research Group in Biomaterials, Biodegradables and Biomimetics-Portugal Government Associate Laboratory, Braga\/Guimar\u00e3es, Portugal 4"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5416-5033","authenticated-orcid":true,"given":"Lingjuan","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6080-0753","authenticated-orcid":true,"given":"Colby","family":"Stotesbury","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6642-5472","authenticated-orcid":true,"given":"Luis J.","family":"Sigal","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 1"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"key":"2023072805020898500_bib1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1084\/jem.20181076","article-title":"Inducible down-regulation of MHC class I results in natural killer cell tolerance","volume":"216","author":"Bern","year":"2019","journal-title":"J. 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