Clonal analysis of Salmonella-specific effector T cells reveals serovar-specific and cross-reactive T cell responses.
Napolitani G., Kurupati P., Teng KWW., Gibani MM., Rei M., Aulicino A., Preciado-Llanes L., Wong MT., Becht E., Howson L., de Haas P., Salio M., Blohmke CJ., Olsen LR., Pinto DMS., Scifo L., Jones C., Dobinson H., Campbell D., Juel HB., Thomaides-Brears H., Pickard D., Bumann D., Baker S., Dougan G., Simmons A., Gordon MA., Newell EW., Pollard AJ., Cerundolo V.
To tackle the complexity of cross-reactive and pathogen-specific T cell responses against related Salmonella serovars, we used mass cytometry, unbiased single-cell cloning, live fluorescence barcoding, and T cell-receptor sequencing to reconstruct the Salmonella-specific repertoire of circulating effector CD4+ T cells, isolated from volunteers challenged with Salmonella enterica serovar Typhi (S. Typhi) or Salmonella Paratyphi A (S. Paratyphi). We describe the expansion of cross-reactive responses against distantly related Salmonella serovars and of clonotypes recognizing immunodominant antigens uniquely expressed by S. Typhi or S. Paratyphi A. In addition, single-amino acid variations in two immunodominant proteins, CdtB and PhoN, lead to the accumulation of T cells that do not cross-react against the different serovars, thus demonstrating how minor sequence variations in a complex microorganism shape the pathogen-specific T cell repertoire. Our results identify immune-dominant, serovar-specific, and cross-reactive T cell antigens, which should aid in the design of T cell-vaccination strategies against Salmonella.