A blend of broadly-reactive and pathogen-selected Vγ4Vγδ1 T cell receptors confer broad bacterial reactivity of resident memory γδ T cells

Abstract

Abstract γδ T cells are pleiotropic sentinels involved in immune defense at barrier tissues. While most γδ T cell subsets are associated with innate-like responses, foodborne Listeria monocytogenes (Lm) infection elicits a substantial resident memory Vγ4Vδ1 T cell response that appears specific to the priming pathogen despite limited T cell receptor (TCR) diversity. As our understanding of memory γδ T cells remains elusive, memory γδ T cells were examined using heterologous challenge infections coupled with TCRδ sequencing to reveal an unanticipated complexity in this memory compartment. CDR3δ sequence analysis revealed that a subset of non-canonical Vδ1 clones expanded during primary and secondary Lm infection but contracted at memory, consistent with antigen-specific clonal expansion. Additionally, canonical clones comprised most of the response, suggesting that some cells may not be Lm-restricted. Indeed, ex vivo stimulation of Lm-elicited memory γδ T cells with Salmonella enterica serovar typhimurium (STm), Yersinia pseudotuberculosis, and Citrobacter rodentium (Cr) induced a robust multifunctional response. Furthermore, heterologous STm-induced colitis infection and intraperitoneal Cr infection of Lm-immune mice led to the TCR-dependent recall of memory γδ T cells, demonstrating their broad reactivity in vivo. Interestingly, most of the non-canonical Vγ4Vδ1 T cell clones that expanded in an antigen-specific manner after Lm infection did not respond after STm infection, suggesting some level of specificity. These findings underscore the complex and promiscuous nature of memory γδ T cells and suggest that pathogen-elicited memory γδ T cells are potential targets for broad-spectrum anti-infective vaccines.