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

Khairallah, Camille; Bettke, Julie A; Gorbatsevych, Oleksandr; Qiu, Zhijuan; Zhang, Yue; Cho, Kyungjin; Kim, Kwang Soon; Chu, Timothy; Imperato, Jessica N; Hatano, Shoji; Romanov, Galina; Yoshikai, Y; Puddington, Lynn; Surh, Charles D.; Bliska, James B.; Velden, Adrianus W. M. van der; Sheridan, Brian S.

doi:10.1038/s41385-021-00447-x

Cited by 8 publications

(11 citation statements)

References 51 publications

(84 reference statements)

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“…Indeed, staining with the newly developed Vγ4-specific antibody 1C10-1F7 suggests that our gating strategy primarily identifies Vγ4 + T cells in the peripheral LN of aged mice (Additional Fig. S 1 ), as recently reported in young adult mice [ 23 ]. Foodborne Lm infection of mice elicited a response from CD44 hi CD27 neg Vγ1.1 neg Vγ2 neg γδ T cells that gradually increased in frequency with mouse age (Fig.…”

Section: Resultssupporting

confidence: 54%

“…Since defective primary conventional T cell responses often lead to reduced memory responses [ 1 , 8 ], we evaluated the impact of aging on the generation of Lm -elicited adaptive γδ T cells in the MLN 9 days post-infection (dpi), at the peak of the primary effector Vγ4 T cell response (Fig. 1 A)[ 15 , 23 ]. Lm -elicited adaptive γδ T cells were identified by the phenotype CD44 hi CD27 neg and expressed the Vγ4Vδ1 TCR, which were identified in the MLN using a dump gate for Vγ1.1 and Vγ2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to providing rapid effector responses, γδ T cells also form adaptive memory populations in barrier tissues of young adult mice in response to infection or inflammation [ 15 – 21 ]. Indeed, our group demonstrated that foodborne Lm infection elicits the generation of an adaptive intestinal resident memory Vγ4Vδ1 T cell population (Garman Vγ TCR nomenclature [ 22 ]) characterized by a CD44 hi CD27 neg phenotype and a broad bacterial reactivity to intestinal pathogens [ 15 , 23 ]. This memory subset has the unusual ability to co-produce IL-17A and IFNγ and participates with conventional T cells in anamnestic protection against reinfection in part through IL-17A production [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2022

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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.

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Section: Resultssupporting

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2022

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“…Balb/c mice were foodborne infected with L . monocytogenes to elicit a population of Vγ1.1/2 - CD44 hi CD27 - γδ T cells as described previously [ 37 , 83 ]. After a return to homeostasis at 30 days post L .…”

Section: Resultsmentioning

confidence: 99%

γδ T cell IFNγ production is directly subverted by Yersinia pseudotuberculosis outer protein YopJ in mice and humans

et al. 2021

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Yersinia pseudotuberculosis is a foodborne pathogen that subverts immune function by translocation of Yersinia outer protein (Yop) effectors into host cells. As adaptive γδ T cells protect the intestinal mucosa from pathogen invasion, we assessed whether Y. pseudotuberculosis subverts these cells in mice and humans. Tracking Yop translocation revealed that the preferential delivery of Yop effectors directly into murine Vγ4 and human Vδ2+ T cells inhibited anti-microbial IFNγ production. Subversion was mediated by the adhesin YadA, injectisome component YopB, and translocated YopJ effector. A broad anti-pathogen gene signature and STAT4 phosphorylation levels were inhibited by translocated YopJ. Thus, Y. pseudotuberculosis attachment and translocation of YopJ directly into adaptive γδ T cells is a major mechanism of immune subversion in mice and humans. This study uncovered a conserved Y. pseudotuberculosis pathway that subverts adaptive γδ T cell function to promote pathogenicity.

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“…Outside of their effects on inflammatory disease, it has been hypothesized that microbiota-specific Trm cells might act as a heterologous defense system, where infection could lead to their re-activation and induction of a generic immune response 120 . Heterologous protection has been demonstrated in principle in the intestine where γδ T cells responding to infection with the Gram positive bacteria Listeria monocytogenes can provide protection against Gram negative Salmonella infections 165 . Additionally, microbiota-specific T cells in the skin offer protection against subsequent skin infection with Candida 131 .…”

Section: Do Microbiota-specific T Cells Form Memory?mentioning

confidence: 99%

Regulation of tissue-resident memory T cells by the Microbiota

Overacre-Delgoffe

Hand

2022

Mucosal Immunology

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Resident memory T cells (Trms) predominantly reside within tissue and are critical for providing rapid protection against invasive viruses, fungi and bacteria. Given that tissues are heavily impacted and shaped by the microbiota, it stands to reason that Trms are also influenced by the microbiota that inhabits barrier sites. The influence of the microbiota is largely mediated by microbial production of metabolites which are crucial to the immune response to both viral infection and cancerous tumors. In addition to the effects of metabolites, antigens derived from the microbiota can activate T cell responses. While microbiota-specific T cells may assist in tissue repair, control of infection and anti-tumor immunity, the actual 'memory' potential of these cells remains unclear. Here, we hypothesize that memory responses to antigens from the microbiota must be 'licensed' by inflammatory signals activated by invasion of the host by microorganisms.

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

Cited by 8 publications

References 51 publications

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

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

γδ T cell IFNγ production is directly subverted by Yersinia pseudotuberculosis outer protein YopJ in mice and humans

Regulation of tissue-resident memory T cells by the Microbiota

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