Retinoic acid signaling during priming licenses intestinal CD103+ CD8 TRM cell differentiation.

CD8 tissue-resident memory T (TRM) cells provide frontline protection at barrier tissues; however, mechanisms regulating TRM cell development are not completely understood. Priming dictates the migration of effector T cells to the tissue, while factors in the tissue induce in situ TRM cell differentiation. Whether priming also regulates in situ TRM cell differentiation uncoupled from migration is unclear. Here, we demonstrate that T cell priming in the mesenteric lymph nodes (MLN) regulates CD103+ TRM cell differentiation in the intestine. In contrast, T cells primed in the spleen were impaired in the ability to differentiate into CD103+ TRM cells after entry into the intestine. MLN priming initiated a CD103+ TRM cell gene signature and licensed rapid CD103+ TRM cell differentiation in response to factors in the intestine. Licensing was regulated by retinoic acid signaling and primarily driven by factors other than CCR9 expression and CCR9-mediated gut homing. Thus, the MLN is specialized to promote intestinal CD103+ CD8 TRM cell development by licensing in situ differentiation.

The accumulation of Vγ4 T cells with aging is associated with an increased adaptive Vγ4 T cell response after foodborne Listeria monocytogenes infection of mice.

BACKGROUND: It is generally accepted that aging has detrimental effects on conventional T cell responses to systemic infections. However, most pathogens naturally invade the body through mucosal barriers. Although mucosal sites are highly enriched in unconventional immune sentinels like γδ T cells, little is currently known about the impact of aging on unconventional mucosal T cell responses. We previously established that foodborne infection with a mouse-adapted internalin A mutant Listeria monocytogenes (Lm) generates an adaptive intestinal memory CD44hi CD27neg Vγ4 T cells capable of co-producing IL-17A and IFNγ. Therefore, we used this model to evaluate the impact of aging on adaptive Vγ4 T cell responses elicited by foodborne infection. RESULTS: Foodborne Lm infection of female Balb/c and C57BL/6 mice led to an increased adaptive CD44hi CD27neg Vγ4 T cell response associated with aging. Moreover, Lm-elicited CD44hi CD27neg Vγ4 T cells maintained diverse functional subsets despite some alterations favoring IL-17A production as mice aged. In contrast to the documented susceptibility of aged mice to intravenous Lm infection, mice contained bacteria after foodborne Lm infection suggesting that elevated bacterial burden was not a major factor driving the increased adaptive CD44hi CD27neg Vγ4 T cell response associated with mouse age. However, CD44hi CD27neg Vγ4 T cells accumulated in naïve mice as they aged suggesting that an increased precursor frequency contributes to the robust Lm-elicited mucosal response observed. Body mass did not appear to have a strong positive association with CD44hi CD27neg Vγ4 T cells within age groups. Although an increased adaptive CD44hi CD27neg Vγ4 T cell response may contribute to foodborne Lm resistance of C57BL/6 mice aged 19 or more months, neither anti-TCRδ or anti-IL-17A treatment impacted Lm colonization after primary infection. These results suggest that γδTCR signaling and IL-17A are dispensable for protection after primary foodborne Lm infection consistent with the role of conventional T cells during the early innate immune response to Lm. CONCLUSIONS: Lm-elicited adaptive Vγ4 T cells appear resistant to immunosenescence and memory Vγ4 T cells could be utilized to provide protective immune functions during enteric infection of aged hosts. As such, oral immunization might offer an efficient therapeutic approach to generate unconventional memory T cells in the elderly.

A blend of broadly-reactive and pathogen-selected Vγ4 Vδ1 T cell receptors confer broad bacterial reactivity of resident memory γδ T cells.

Although murine γδ 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 γδ T cells. Here, we interrogated intestinal memory Vγ4 Vδ1 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 Vδ1 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 Vγ4 Vδ1 T cells are broadly reactive. The Vγ4 Vδ1 T cell recall response to Lm, Salmonella enterica serovar Typhimurium (STm) and Citrobacter rodentium was largely mediated by the γδTCR as internalizing the γδTCR prevented T cell expansion. Both broadly-reactive canonical and pathogen-selected non-canonical Vδ1 clones contributed to memory responses to Lm and STm. Interestingly, some non-canonical γδ 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 γδ T cells and suggest that pathogen-elicited memory γδ T cells are potential targets for broad-spectrum anti-infective vaccines.