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Transforming growth factor \u03b2 (TGF-\u03b2) is a potent immune suppressor that is upregulated early upon viral infection and maintained during chronic infections in both mice and humans. However, the role of TGF-\u03b2 signaling in regulating individual cell types<jats:italic>in vivo<\/jats:italic>is still unclear. Using infections with two different persistent viruses, murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV; Cl13), in their natural rodent host, we observed that TGF-\u03b2 signaling on dendritic cells (DCs) did not dampen DC maturation or cytokine production in the early stages of chronic infection with either virus<jats:italic>in vivo<\/jats:italic>. In contrast, TGF-\u03b2 signaling prior to (but not during) chronic viral infection directly restricted the natural killer (NK) cell number and effector function. This restriction likely compromised both the early control of and host survival upon MCMV infection but not the long-term control of LCMV infection. These data highlight the context and timing of TGF-\u03b2 signaling on different innate cells that contribute to the early host response, which ultimately influences the outcome of chronic viral infection<jats:italic>in vivo<\/jats:italic>.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold><jats:italic>In vivo<\/jats:italic>host responses to pathogens are complex processes involving the cooperation of many different immune cells migrating to specific tissues over time, but these events cannot be replicated<jats:italic>in vitro<\/jats:italic>. Viruses causing chronic infections are able to subvert this immune response and represent a human health burden. Here we used two well-characterized viruses that are able to persist in their natural mouse host to dissect the role of the suppressive molecule TGF-\u03b2 in dampening host responses to infection<jats:italic>in vivo<\/jats:italic>. This report presents information that allows an increased understanding of long-studied TGF-\u03b2 signaling by examining its direct effect on different immune cells that are activated very early after<jats:italic>in vivo<\/jats:italic>viral infection and may aid with the development of new antiviral therapeutic strategies.<\/jats:p>","DOI":"10.1128\/jvi.03076-14","type":"journal-article","created":{"date-parts":[[2015,1,15]],"date-time":"2015-01-15T06:31:23Z","timestamp":1421303483000},"page":"3343-3355","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Constitutive but Not Inducible Attenuation of Transforming Growth Factor \u03b2 Signaling Increases Natural Killer Cell Responses without Directly Affecting Dendritic Cells Early after Persistent Viral Infection"],"prefix":"10.1128","volume":"89","author":[{"given":"Gavin M.","family":"Lewis","sequence":"first","affiliation":[{"name":"Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Macal","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles R.","family":"Hesser","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elina I.","family":"Zu\u00f1iga","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1070884"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1168676"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115059"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.8.3926"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2893.1997.00124.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.1.39"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.06.015"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni736"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/embj.201488027"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20011672"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198687"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-08-303123"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10624"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2004.07.040"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1118834109"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/359693a0"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.07.012"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.03.017"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.8.5194"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-9966-8_50"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.5.2690"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/stem.150144"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI20243"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2008.08.016"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0909635"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002594"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-03-1100"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.15.8299-8309.2003"},{"key":"e_1_3_2_30_2","doi-asserted-by":"crossref","first-page":"4874","DOI":"10.4049\/jimmunol.151.9.4874","article-title":"Transforming growth factor-beta expression and natural killer cell responses during virus infection of normal, nude, and SCID mice","volume":"151","author":"Su HC","year":"1993","unstructured":"Su HC, Ishikawa R, Biron CA. 1993. 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