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

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. [Display omitted] •CD4+ T cells recognize a conserved bacterial epitope from pneumolysin (Ply427–441)•Ply427–441 is presented by the globally abundant HLA allomorphs DPB1∗02 and DPB1∗04•Ply427–441 is recognized by architecturally diverse TCRs in the context of HLA-DPB1∗04•Cross-recognition of related epitopes generates trans-phyla bacterial immunity CD4+ T cell-mediated immunity protects against infection with Streptococcus pneumoniae (pneumococcus), but the relevant antigens have not been identified previously. Ciacchi et al. show that near-ubiquitous CD4+ T cell reactivity against a conserved epitope from the pneumococcal cholesterol-dependent cytolysin (CDC) pneumolysin generates trans-phyla immunity against divergent bacterial pathogens encoding CDCs.