Pathogen-elicited memory γδ T cells express a broadly reactive canonical TCR or a pathogen-specific non-canonical TCR

Abstract γδ T cells are critical sentinels protecting barrier surfaces against pathogens. However, our understanding of γδ T cell specificity remains limited. We previously identified a resident memory Vγ4Vδ1 T cell population elicited by foodborne Listeria monocytogenes (Lm) infection. Analysis of the CDR3δ sequences revealed that a large subset of non-canonical clones expanded during primary Lm infection, contracted during memory homeostasis and recalled after secondary Lm infection suggesting antigenic-specificity may be involved in this response. However, most of the response was elicited by cells bearing a canonical Vδ1 TCR suggesting that many Lm-elicited cells may not be Lm-specific. Indeed, stimulation of mesenteric lymph node cells from Lm-immune mice with diverse pathogens induced a functional response by Lm-elicited memory γδ T cells. Similarly, induction of Salmonella colitis (STm-colitis) in Lm-immune mice resulted in a TCR-dependent γδ T cell recall-like response, demonstrating that the majority of these memory cells respond to heterologous infection. Interestingly, most of the non-canonical γδ T cell clones that responded to Lm infection did not expand in response to STm-colitis suggesting some level of specificity is imparted by the priming pathogen. Importantly, other enteropathogens triggered a recall-like response of Lm-elicited memory γδ T cells. Adaptive γδ T cells were also generated after foodborne infection of germ-free mice and in response to diverse bacterial infections of SPF mice, indicating that this population can be induced by a broad range of disseminating pathogens and may provide a broad target for universal mucosal vaccines of the gut.