Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus

Gebhardt, Thomas; Wakim, Linda M.; Eidsmo, Liv; Reading, Patrick C.; Heath, William R.; Carbone, Federico

doi:10.1038/ni.1718

Cited by 991 publications

(1,234 citation statements)

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“…This local proliferation also explains the observations of lymphoid follicles observed in the stomach after long-term infection [47]. Recently, local recall memory responses in peripheral non-lymphoid tissues at least for CD8 1 T cells have been shown to act to control herpes simplex infection [48]. Our data would indicate a similar local recall response for CD4 1 T cells occurs in the stomach for H. pylori infection.…”

Section: Discussionsupporting

confidence: 85%

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

Becher¹,

Deutscher²,

Simpfendorfer³

et al. 2010

Eur J Immunol

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Helicobacter pylori is recognised as the chief cause of chronic gastritis, ulcers and gastric cancer in humans. With increased incidence of treatment failure and antibiotic resistance, development of prophylactic or therapeutic vaccination is a desirable alternative. Although the results of vaccination studies in animal models have been promising, studies in human volunteers have revealed problems such as 'post-immunisation gastritis' and comparatively poor responses to vaccine antigens. The focus of this study was to compare the gastric and systemic cellular immune responses induced by recombinant attenuated Salmonella Typhimurium-based vaccination in the C57BL/6 model of H. pylori infection. Analysis of lymphocyte populations in the gastric mucosa, blood, spleen, paragastric LN and MLN revealed that the effects of vaccination were largely confined to the parenchymal stomach rather than lymphoid organs. Vaccine-induced protection was correlated with an augmented local recall response in the gastric mucosa, with increased proportions of CD4 1 T cells, neutrophils and reduced proportions of CD4 1 Treg. CD4 1 T cells isolated from the stomachs of vaccinated mice proliferated ex vivo in response to H. pylori antigen, and secreted Th1 cytokines, particularly IFN-c. This detailed analysis of local gastric immune responses provides insight into the mechanism of vaccine-induced protection.Key words: Helicobacter pylori . Stomach . Treg cells . Vaccine IntroductionHelicobacter pylori is a Gram-negative spiral bacterium that infects the mucous gel layer of the human stomach. Infection is chronic and causes a range of diseases ranging from acute to chronic gastritis, ulcers and, in a small proportion of patients, gastric adenocarcinoma [1].The treatment of H. pylori disease is not straightforward. The most commonly used combination antibiotic therapy, amoxicillin plus clathromycin and a proton pump inhibitor, now only achieve a cure in o80% of cases [2]. This efficacy rate is substantially less than the 495% rate that is deemed acceptable for most other infectious diseases. A prophylactic or therapeutic vaccine would be a cost-effective way to control H. pylori-induced disease.Vaccination is effective in animal models, with 10-to 100-fold reductions (but not sterile immunity) in bacterial colonisation reported in a variety of experimental animals, following immunisation by either oral or parenteral routes (reviewed in [3][4][5]). Oral (mucosal route) vaccination is desirable for a human H. pylori vaccine because of the ease of delivery and, for a live vaccine, the necessity of a single dose is also attractive. 2778with issues such as poor immunogenicity [6], and adverse reactions [7], presenting serious obstacles to further progression of a human vaccine [8]. The reasons for this failure probably result from apparently opposing aspects of the immune response to vaccination. On the one hand vaccination causes 'post-immunisation gastritis' a local inflammatory responses in the stomach in many animal and human recipients, a...

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Section: Discussionsupporting

confidence: 85%

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

Becher¹,

Deutscher²,

Simpfendorfer³

et al. 2010

Eur J Immunol

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“…Recognizing that resident T cells can be identified by the presence of CD69 and CD103 (Gebhardt et al., 2009), in preliminary studies we determined CD69 and CD103 expressions (Figure S1b). CD69 was widely expressed on FRT T cells, while CD103 expression was more restricted.…”

Section: Resultsmentioning

confidence: 99%

“…Following antigen recognition, naïve T cells differentiate into effector and memory T cells. Tissue‐resident memory T cells (TRMs) are a subset of memory cells that remain in tissues and do not recirculate (Gebhardt et al., 2009; Mueller & Mackay, 2016). CD8 + TRMs can be identified by the expression of CD69 and CD103, the αE portion of the αEβ7 integrin that allows interactions with E‐cadherin expressed on epithelial cells (Rosato, Beura & Masopust, 2017).…”

Section: Introductionmentioning

confidence: 99%

Aging impacts CD103⁺CD8⁺ T cell presence and induction by dendritic cells in the genital tract

et al. 2018

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SummaryAs women age, susceptibility to systemic and genital infections increases. Tissue‐resident memory T cells (TRMs) are CD103+ CD8+ long‐lived lymphocytes that provide critical mucosal immune protection. Mucosal dendritic cells (DCs) are known to induce CD103 expression on CD8+ T cells. While CD103+ CD8+ T cells are found throughout the female reproductive tract (FRT), the extent to which aging impacts their presence and induction by DCs remains unknown. Using hysterectomy tissues, we found that endometrial CD103+ CD8+ T cells were increased in postmenopausal compared to premenopausal women. Endometrial DCs from postmenopausal women were significantly more effective at inducing CD103 expression on allogeneic naïve CD8+ T cells than DCs from premenopausal women; CD103 upregulation was mediated through membrane‐bound TGFβ signaling. In contrast, cervical CD103+ T cells and DC numbers declined in postmenopausal women with age. Decreases in DCs correlated with decreased CD103+ T cells in endocervix, but not ectocervix. Our findings demonstrate a previously unrecognized compartmentalization of TRMs in the FRT of postmenopausal women, with loss of TRMs and DCs in the cervix with aging, and increased TRMs and DC induction capacity in the endometrium. These findings are relevant to understanding immune protection in the FRT and to the design of vaccines for women of all ages.

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“…Evidence from murine experiments and studies of T cell depletion in human skin T cell malignancies (leukemic CTCL and mycosis fungoides) suggest that central memory T cells from skin regularly recirculate, whereas this is not the case for skin effector memory cells (28,29). However, the possibility of migration to the draining LN (but not recirculation to other tissues) following Ag stimulation was not excluded, especially for CD4 + T cells, and indeed, it is reported that some patients with malignant disease of effector memory T cells (mycosis fungoides) can develop LN involvement (28).…”

Section: Discussionmentioning

confidence: 99%

Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery

Tatović

Young

Kochba³

et al. 2015

The Journal of Immunology

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Assessment of immune responses in lymph nodes (LNs) is routine in animals, but rarely done in humans. We have applied minimally invasive ultrasound-guided fine-needle aspiration of the LN to a before-and-after study of the immune response to intradermally delivered Ag in healthy volunteers (n = 25). By comparison with PBMCs from the same individual, LN cells (LNCs) were characterized by reduced numbers of effector memory cells, especially CD8+ TEMRA cells (3.37 ± 1.93 in LNCs versus 22.53 ± 7.65 in PBMCs; p = 0.01) and a marked increased in CD69 expression (27.67 ± 7.49 versus 3.49 ± 2.62%, LNCs and PBMCs, respectively; p < 0.0001). At baseline, there was a striking absence of IFN-γ ELISPOT responses to recall Ags (purified protein derivative, Tetanus toxoid, or flu/EBV/CMV viral mix) in LN, despite strong responses in the peripheral blood. However, 48 h after tuberculin purified protein derivative administration in the ipsilateral forearm resulting in a positive skin reaction, a clear increase in IFN-γ ELISPOT counts was seen in the draining LN but not in PBMCs. This response was lost by 5 d. These data suggest that the low levels of effector memory cells in the LN may explain the low background of baseline ELISPOT responses in LNs as compared with PBMCs, and the appearance of a response after 48 h is likely to represent migration of effector memory cells from the skin to the LN. Hence, it appears that the combination of intradermal Ag administration and draining LN sampling can be used as a sensitive method to probe the effector memory T cell repertoire in the skin.

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Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus

Cited by 991 publications

References 46 publications

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

Aging impacts CD103⁺CD8⁺ T cell presence and induction by dendritic cells in the genital tract

Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery

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Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus

Cited by 991 publications

References 46 publications

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

Aging impacts CD103+CD8+ T cell presence and induction by dendritic cells in the genital tract

Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery

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Aging impacts CD103⁺CD8⁺ T cell presence and induction by dendritic cells in the genital tract