Broadly reactive human CD4⁺ T cells against Enterobacteriaceae are found in the naïve repertoire and are clonally expanded in the memory repertoire

Abstract

Enterobacteriaceae are a large family of Gram‐negative bacteria that includes both commensals and opportunistic pathogens. The latter can cause severe nosocomial infections, with outbreaks of multi‐antibiotics resistant strains, thus being a major public health threat. In this study, we report that Enterobacteriaceae‐reactive memory Th cells were highly enriched in a CCR6+CXCR3+ Th1*/17 cell subset and produced IFN‐γ, IL‐17A, and IL‐22. This T cell subset was severely reduced in septic patients with K. pneumoniae bloodstream infection who also selectively lacked circulating K. pneumonie‐reactive T cells. By combining heterologous antigenic stimulation, single cell cloning and TCR Vβ sequencing, we demonstrate that a large fraction of memory Th cell clones was broadly cross‐reactive to several Enterobacteriaceae species. These cross‐reactive Th cell clones were expanded in vivo and a large fraction of them recognized the conserved outer membrane protein A antigen. Interestingly, Enterobacteriaceae broadly cross‐reactive T cells were also prominent among in vitro primed naïve T cells. Collectively, these data point to the existence of immunodominant T cell epitopes shared among different Enterobacteriaceae species and targeted by cross‐reactive T cells that are readily found in the pre‐immune repertoire and are clonally expanded in the memory repertoire.

The contribution of uncharted RNA sequences to tumor identity in lung adenocarcinoma

“…One contig was strongly repressed in tumors and corresponded to Klebsiella pneumoniae large subunit rRNA. Indeed, Klebsiella is a common lung bacterium against which cross-reactive T-cells are present in the naive CD4+ T-cell repertoire [50]. Our results thus suggest the joint occurrence of Klebsiella and matching CD4+ T-cell in normal lungs, and their disappearance in tumors.…”

The contribution of uncharted RNA sequences to tumor identity in lung adenocarcinoma

“…One of them was strongly repressed in tumors and matched a Klebsiella pneumoniae rRNA fragment. Klebsiella is a common lung bacterium against which cross-reactive T-cells are present in the naive CD4+ T-cell repertoire ( 53 ). This result thus suggests the joint occurrence of Klebsiella and matching CD4+ T-cell in normal lungs, and their disappearance in tumors.…”

Clonal composition and persistence of antigen‐specific circulating T follicular helper cells

“…The finding that cT FH and non‐cT FH cells responded to different extents to antigenic stimulations prompted us to further investigate their lineage relationship. Using a previously established workflow [ 19 , 22 ], we isolated CFSE low cells from the antigen‐stimulated cultures and performed next‐generation sequencing to quantify and compare TCR Vβ clonotypes of different antigen‐specific T cell populations. As shown in Fig.…”