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

Abstract

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.

From Host Defense to Metabolic Signatures: Unveiling the Role of γδ T Cells in Bacterial Infections

“…A similar γδ T cell population was found in an imiquimod sensitization model of psoriasis, in which they produced elevated levels of IL-17, upregulated IL-1R1 expression, and increasingly responded to IL-1β stimulation [64]. Interestingly, memory Vγ4+ γδ T cells were resistant to cellular senescence [100]. Their adaptive-like response to food-borne L. monocytogenes infection increased with age, making these memory T cells an essential target for antibacterial therapies in elderly patients [100].…”

“…Interestingly, memory Vγ4+ γδ T cells were resistant to cellular senescence [100]. Their adaptive-like response to food-borne L. monocytogenes infection increased with age, making these memory T cells an essential target for antibacterial therapies in elderly patients [100]. Thus, γδ T cells have multi-faceted functions, including early protection, inflammatory resolution, and memory functions, during L. monocytogenes infection.…”

Aging unconventionally: γδ T cells, iNKT cells, and MAIT cells in aging

“…In mice, there has also been reports of shifting Vγ/Vδ usage with age, similar to humans. Aging has been shown to lead to increased infection-induced mucosal adaptive Vγ4+ T cells in mice during Listeria monocytogenes infection [91] , as well as during West Nile Virus (WNV) infection, which was associated with a higher mortality to WNV encephalitis in aged mice [92] . This increase in Vγ4+ T cells with age has a resemblance to human Vδ1+ cells, which similarly are expanded or maintained with age [93] .…”

“…Aging is also associated with susceptibility to enteropathogenic L. monocytogenes, with a high mortality rate of 20% of infected individuals > 65 years old [91] . γδ T cells are protective in L. monocytogenes infections, where there is an age-dependent accumulation of Vγ4+ T cells [91] .…”

“…Aging is also associated with susceptibility to enteropathogenic L. monocytogenes, with a high mortality rate of 20% of infected individuals > 65 years old [91] . γδ T cells are protective in L. monocytogenes infections, where there is an age-dependent accumulation of Vγ4+ T cells [91] . iNKT cells have been suggested to be important for clearance of Pseudomonas aeruginosa from the lungs [248] , as well as prevention of joint inflammation after Borrelia burgdorferi infection [249] .…”