PMID- 37100059 OWN - NLM STAT- MEDLINE DCOM- 20230512 LR - 20230517 IS - 1097-4180 (Electronic) IS - 1074-7613 (Linking) VI - 56 IP - 5 DP - 2023 May 9 TI - CD4(+) T cell-mediated recognition of a conserved cholesterol-dependent cytolysin epitope generates broad antibacterial immunity. PG - 1082-1097.e6 LID - S1074-7613(23)00140-1 [pii] LID - 10.1016/j.immuni.2023.03.020 [doi] AB - CD4(+) T cell-mediated immunity against Streptococcus pneumoniae (pneumococcus) can protect against recurrent bacterial colonization and invasive pneumococcal diseases (IPDs). Although such immune responses are common, the pertinent antigens have remained elusive. We identified an immunodominant CD4(+) T cell epitope derived from pneumolysin (Ply), a member of the bacterial cholesterol-dependent cytolysins (CDCs). This epitope was broadly immunogenic as a consequence of presentation by the pervasive human leukocyte antigen (HLA) allotypes DPB1( *)02 and DPB1( *)04 and recognition via architecturally diverse T cell receptors (TCRs). Moreover, the immunogenicity of Ply(427-444) was underpinned by core residues in the conserved undecapeptide region (ECTGLAWEWWR), enabling cross-recognition of heterologous bacterial pathogens expressing CDCs. Molecular studies further showed that HLA-DP4-Ply(427-441) was engaged similarly by private and public TCRs. Collectively, these findings reveal the mechanistic determinants of near-global immune focusing on a trans-phyla bacterial epitope, which could inform ancillary strategies to combat various life-threatening infectious diseases, including IPDs. CI - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Ciacchi, Lisa AU - Ciacchi L AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. FAU - van de Garde, Martijn D B AU - van de Garde MDB AD - Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Utrecht 3721MA, the Netherlands. FAU - Ladell, Kristin AU - Ladell K AD - Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff CF14 4XN, UK. FAU - Farenc, Carine AU - Farenc C AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. FAU - Poelen, Martien C M AU - Poelen MCM AD - Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Utrecht 3721MA, the Netherlands. FAU - Miners, Kelly L AU - Miners KL AD - Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff CF14 4XN, UK. FAU - Llerena, Carmen AU - Llerena C AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. FAU - Reid, Hugh H AU - Reid HH AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. FAU - Petersen, Jan AU - Petersen J AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. FAU - Price, David A AU - Price DA AD - Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff CF14 4XN, UK; Systems Immunity Research Institute, Cardiff University School of Medicine, University Hospital of Wales, Cardiff CF14 4XN, UK. Electronic address: priced6@cardiff.ac.uk. FAU - Rossjohn, Jamie AU - Rossjohn J AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff CF14 4XN, UK; Systems Immunity Research Institute, Cardiff University School of Medicine, University Hospital of Wales, Cardiff CF14 4XN, UK. Electronic address: jamie.rossjohn@monash.edu. FAU - van Els, Cecile A C M AU - van Els CACM AD - Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Utrecht 3721MA, the Netherlands; Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht 3584CL, the Netherlands. Electronic address: cecile.van.els@rivm.nl. LA - eng GR - 100326/Z/12/Z/WT_/Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230425 PL - United States TA - Immunity JT - Immunity JID - 9432918 RN - 0 (Cytotoxins) RN - 0 (Epitopes, T-Lymphocyte) RN - 97C5T2UQ7J (Cholesterol) SB - IM MH - Humans MH - *Cytotoxins MH - *CD4-Positive T-Lymphocytes MH - Bacteria MH - Epitopes, T-Lymphocyte MH - Cholesterol OTO - NOTNLM OT - CD4(+) T cells OT - HLA-DP OT - Streptococcus pneumoniae OT - TCR repertoire OT - cholesterol-dependent cytolysin OT - epitope OT - human immunology OT - listeriolysin O OT - perfringolysin O OT - streptolysin O COIS- Declaration of interests The authors declare no competing interests. EDAT- 2023/04/27 00:42 MHDA- 2023/05/12 07:06 CRDT- 2023/04/26 18:42 PHST- 2022/08/18 00:00 [received] PHST- 2022/12/31 00:00 [revised] PHST- 2023/03/30 00:00 [accepted] PHST- 2023/05/12 07:06 [medline] PHST- 2023/04/27 00:42 [pubmed] PHST- 2023/04/26 18:42 [entrez] AID - S1074-7613(23)00140-1 [pii] AID - 10.1016/j.immuni.2023.03.020 [doi] PST - ppublish SO - Immunity. 2023 May 9;56(5):1082-1097.e6. doi: 10.1016/j.immuni.2023.03.020. Epub 2023 Apr 25.