CD4+ T cell-mediated recognition of a conserved cholesterol-dependent cytolysin epitope generates broad antibacterial immunity

Ciacchi, Lisa, van de Garde, Martijn D.B., Ladell, Kristin ORCID: https://orcid.org/0000-0002-9856-2938, Farenc, Carine, Poelen, Martien C.M., Miners, Kelly L., Llerena, Carmen, Reid, Hugh H., Petersen, Jan, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 and van Els, Cécile A.C.M. 2023. CD4+ T cell-mediated recognition of a conserved cholesterol-dependent cytolysin epitope generates broad antibacterial immunity. Immunity 56 (5) , pp. 1082-1097. 10.1016/j.immuni.2023.03.020

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	1074-7613
Date of First Compliant Deposit:	26 May 2023
Date of Acceptance:	30 March 2023
Last Modified:	31 May 2023 06:24
URI:	https://orca.cardiff.ac.uk/id/eprint/159994

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