@article{e67e66a7420747b5a36a46f1b463c3bb,
title = "CD4+ T cell-mediated recognition of a conserved cholesterol-dependent cytolysin epitope generates broad antibacterial immunity",
abstract = "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 Ply427–444 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-Ply427–441 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.",
keywords = "CD4 T cells, cholesterol-dependent cytolysin, epitope, HLA-DP, human immunology, listeriolysin O, perfringolysin O, Streptococcus pneumoniae, streptolysin O, TCR repertoire",
author = "Lisa Ciacchi and {van de Garde}, {Martijn D.B.} and Kristin Ladell and Carine Farenc and Poelen, {Martien C.M.} and Miners, {Kelly L.} and Carmen Llerena and Reid, {Hugh H.} and Jan Petersen and Price, {David A.} and Jamie Rossjohn and {van Els}, {C{\'e}cile A.C.M.}",
note = "Funding Information: We thank Josien Lanfermeijer (RIVM/IIV) for technical support, Frans Reubsaet (RIVM/IDS) for providing clinical bacterial isolates, Marien de Jonge (Radboud UMC) for providing TIGR4 ΔCPS , Sanofi Pasteur for providing Ply and dPly, the NIH Tetramer Core Facility for providing the HLA-DP ∗ 02/ECT and HLA-DP ∗ 04/ECT tetramers, and staff at the Monash Macromolecular Crystallization Facility and the Australian Synchrotron (beamlines MX1 and MX2) for assistance with crystallization and data collection, respectively. This study was funded by the Dutch Ministry of Health, Welfare and Sport (VWS). D.A.P. was supported by a Wellcome Trust Senior Investigator Award ( 100326/Z/12/Z ). J.R. was supported by an NHMRC Investigator Award (L3) . Funding Information: We thank Josien Lanfermeijer (RIVM/IIV) for technical support, Frans Reubsaet (RIVM/IDS) for providing clinical bacterial isolates, Marien de Jonge (Radboud UMC) for providing TIGR4ΔCPS, Sanofi Pasteur for providing Ply and dPly, the NIH Tetramer Core Facility for providing the HLA-DP∗02/ECT and HLA-DP∗04/ECT tetramers, and staff at the Monash Macromolecular Crystallization Facility and the Australian Synchrotron (beamlines MX1 and MX2) for assistance with crystallization and data collection, respectively. This study was funded by the Dutch Ministry of Health, Welfare and Sport (VWS). D.A.P. was supported by a Wellcome Trust Senior Investigator Award (100326/Z/12/Z). J.R. was supported by an NHMRC Investigator Award (L3). L.C. M.D.B.v.d.G. and K.L. performed experiments, analyzed data, and wrote the paper; C.F. M.C.M.P. K.L.M. C.L. H.H.R. and J.P. provided reagents/resources, and/or performed experiments, and/or analyzed data; D.A.P. J.R. and C.A.C.M.v.E. conceived the project, led the study, supervised the work, and wrote the paper. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = may,
day = "9",
doi = "10.1016/j.immuni.2023.03.020",
language = "English",
volume = "56",
pages = "1082--1097.e6",
journal = "Immunity",
issn = "1074-7613",
publisher = "Elsevier",
number = "5",
}
