biostudies-literatureMarkov NSNCATS NIH HHSNIA NIH HHSNIAID NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesNIEHS NIH HHSAmerican Heart Association-American Stroke AssociationNHLBI NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)NLM NIH HHSNCI NIH HHSNIH HHSCSRD VA1607-1622https://www.ebi.ac.uk/biostudies/studies/S-EPMC11490290biostudies-literatureUnknown25(9)The evolution of T cell molecular signatures in the distal lung of patients with severe pneumonia is understudied. Here, we analyzed T cell subsets in longitudinal bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia, including unvaccinated patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with respiratory failure not linked to pneumonia. In patients with SARS-CoV-2 pneumonia, activation of interferon signaling pathways, low activation of the NF-κB pathway and preferential targeting of spike and nucleocapsid proteins early after intubation were associated with favorable outcomes, whereas loss of interferon signaling, activation of NF-κB-driven programs and specificity for the ORF1ab complex late in disease were associated with moNature immunologyDistinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia.PMC11490290R01 HL153122R01 HL134800F32 HL162377R01 HL158139R21 AG075423F31 AG071225R01 AI177498R01 LM013337UL1 TR001422K23 HL169815R01 HL149883T32 AG020506T32 AI007476I01 CX001777R01 HL094643T32 HL076139P30 CA060553P01 AG049665S10 OD032243R01 HL147290R01 HL153312P01 HL154998U19 AI135964U01 TR003528U19 AI181102R01 ES034350R01 HL14757524PRE1196998U19AI135964Fiala JASecunda KShen JMahmoud APawlowski AERasmussen LHartmann EMSmith-Nunez AGottardi CJLaurenzo SGrant RAKidd DAMalsin ESPickens COPatel RGo PDGao CABolig TRidge KMOlson EMSimons LMClepp RKPerez-Leonor XGRowe TBudinger GRSBorkowski NSwaminathan SJain MWunderink RGSimmons LLeibenguth EMNwaezeapu JColeman JDonnelly HKNunes Amaral LALiu GYSala MAMcQuattie-Pimentel ACOzer EASznajder JIArnold JMRen ZChandel NSHan SBartom ETCuttica MJWolfe ARSchroedl CJSchneider DKamp DWSeed PCYu ZMatias GHukamdad MGadhvi GTWhite BNU SCRIPT Study InvestigatorsQuerrey MTran BRios-Guzman EVitale KMeza DShanes EDHultquist JGuzman ERGatesy SWMLomasney JWQi CKihshen HMarkov NSLu ZWagh AAYeldandi AVDonayre AWalter JMHorvath CMStoeger TRosenbaum MLKandpal MMylvaganam RJSenkow KJLombardo TAKang MSichizya LPrickett MHWehbe FRussell SRStarren JGreen SJHelmin KAShilatifard ABharat ASporn PHSCastellanos JHauser ARPoor TADematte JEMisharin AVSzabo AMorales-Nebreda LHyder SMJoudi AMNannapaneni PSinger BDDiaz EAlisoltanidehkordi ASumner JThakkar SJohnson LRosenberg SRTextor LNLorenzo-Redondo RLudwig ACybulski TRRasmussen LVRowell JJonasson ETomic RAbdala-Valencia HDeters JSKruser JMJovisic MBailey JILevenson ARGradone LDHultquist JFPolitanska YWinter DRGusman ELawrence RKadar RBSmith SKalhan RWolfe LFAlexander MJKorth EAKlug ZMGates KLNozick SfalseDistinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia.The evolution of T cell molecular signatures in the distal lung of patients with severe pneumonia is understudied. Here, we analyzed T cell subsets in longitudinal bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia, including unvaccinated patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with respiratory failure not linked to pneumonia. In patients with SARS-CoV-2 pneumonia, activation of interferon signaling pathways, low activation of the NF-κB pathway and preferential targeting of spike and nucleocapsid proteins early after intubation were associated with favorable outcomes, whereas loss of interferon signaling, activation of NF-κB-driven programs and specificity for the ORF1ab complex late in disease were associated with mo2024-01-01T00:00:00Z2024 Sep2026-05-29T10:26:04.665Z2026-04-08T04:27:40.111ZS-EPMC114902903913838410.1038/s41590-024-01914-w