Broadly reactive human CD4 <sup>+</sup> T cells against Enterobacteriaceae are found in the naïve repertoire and are clonally expanded in the memory repertoire
Antonino Cassotta, Jérémie D. Goldstein, Greta Durini, David Jarrossay, Franca Baggi Menozzi, Mario Venditti, Alessandro Russo, Marco Falcone, Antonio Lanzavecchia, Maria Cristina Gagliardi, Daniela Latorre, Federica Sallusto
Abstract
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.