A blend of broadly-reactive and pathogen-selected V gamma 4 V delta 1 T cell receptors confer broad bacterial reactivity of resident memory gamma delta T cells

Abstract

Although murine gamma delta T cells are largely considered innate immune cells, they have recently been reported to form long-lived memory populations. Much remains unknown about the biology and specificity of memory gamma delta T cells. Here, we interrogated intestinal memory V gamma 4 V delta 1 T cells generated after foodborne Listeria monocytogenes (Lm) infection to uncover an unanticipated complexity in the specificity of these cells. Deep TCR sequencing revealed that a subset of non-canonical V delta 1 clones are selected by Lm infection, consistent with antigen-specific clonal expansion. Ex vivo stimulations and in vivo heterologous challenge infections with diverse pathogenic bacteria revealed that Lm-elicited memory V gamma 4 V delta 1 T cells are broadly reactive. The V gamma 4 V delta 1 T cell recall response to Lm, Salmonella enterica serovar Typhimurium (STm) and Citrobacter rodentium was largely mediated by the gamma delta TCR as internalizing the gamma delta TCR prevented T cell expansion. Both broadly-reactive canonical and pathogen-selected non-canonical V delta 1 clones contributed to memory responses to Lm and STm. Interestingly, some non-canonical gamma delta T cell clones selected by Lm infection also responded after STm infection, suggesting some level of cross-reactivity. These findings underscore the promiscuous nature of memory gamma delta T cells and suggest that pathogen-elicited memory gamma delta T cells are potential targets for broad-spectrum anti-infective vaccines.