Tissue resident T cell memory or how the magnificent seven are chilling in the bone

Zens, Kyra D.; Münz, Christian

doi:10.1002/eji.201948208

Cited by 3 publications

(2 citation statements)

References 34 publications

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“…Thus, in addition to systemic injection of blockade MAbs, a direct delivery of single-chain variablefragment Fc (scFv-Fc) Abs using engendered adeno-associated virus (AAV) vectors may avoid unwanted systemic immune-related adverse events (IRAE) associated with the use of systemically delivered checkpoint inhibitors (61). If local delivery of LAG-3 and PD-1 checkpoint inhibitors directly into cornea and TG causes uncontrolled local inflammation, we are currently considering using an inducible tissue-specific promoter that will be turned on/off (62) or selectively stimulated by reactivated HSV-1 locally within TG (63). Moreover, the timing of delivery and dosage of blockade MAbs that would result in clinical efficacy with little to no side effects are being considered, and the results will be the subject of future reports.…”

Section: Discussionmentioning

confidence: 99%

Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4⁺T_EMCells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice

Srivastava

Coulon

Prakash

et al. 2020

J Virol

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While the role of CD8+ T cells in the control of herpes simplex virus 1 (HSV-1) infection and disease is gaining wider acceptance, a direct involvement of effector CD4+ T cells in this protection and the phenotype and function of HSV-specific human CD4+ T cell epitopes remain to be fully elucidated. In the present study, we report that several epitopes from the HSV-1 virion tegument protein (VP11/12) encoded by UL46 are targeted by CD4+ T cells from HSV-seropositive asymptomatic individuals (who, despite being infected, never develop any recurrent herpetic disease). Among these, we identified two immunodominant effector memory CD4+ TEM cell epitopes, amino acids (aa) 129 to 143 of VP11/12 (VP11/12129–143) and VP11/12483–497, using in silico, in vitro, and in vivo approaches based on the following: (i) a combination of the TEPITOPE algorithm and PepScan library scanning of the entire 718 aa of HSV-1 VP11/12 sequence; (ii) an in silico peptide-protein docking analysis and in vitro binding assay that identify epitopes with high affinity to soluble HLA-DRB1 molecules; and (iii) an ELISpot assay and intracellular detection of gamma interferon (IFN-γ), CD107a/b degranulation, and CD4+ T cell carboxyfluorescein succinimidyl ester (CFSE) proliferation assays. We demonstrated that native VP11/12129–143 and VP11/12483–497 epitopes presented by HSV-1-infected HLA-DR-positive target cells were recognized mainly by effector memory CD4+ TEM cells while being less targeted by FOXP3+ CD4+ CD25+ regulatory T cells. Furthermore, immunization of HLA-DR transgenic mice with a mixture of the two immunodominant human VP11/12 CD4+ TEM cell epitopes, but not with cryptic epitopes, induced HSV-specific polyfunctional IFN-γ-producing CD107ab+ CD4+ T cells associated with protective immunity against ocular herpes infection and disease. IMPORTANCE We report that naturally protected HSV-1-seropositive asymptomatic individuals develop a higher frequency of antiviral effector memory CD4+ TEM cells specific to two immunodominant epitopes derived from the HSV-1 tegument protein VP11/12. Immunization of HLA-DR transgenic mice with a mixture of these two immunodominant CD4+ T cell epitopes induced a robust antiviral CD4+ T cell response in the cornea that was associated with protective immunity against ocular herpes. The emerging concept of developing an asymptomatic herpes vaccine that would boost effector memory CD4+ and CD8+ TEM cell responses is discussed.

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Section: Discussionmentioning

confidence: 99%

Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4⁺T_EMCells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice

Srivastava

Coulon

Prakash

et al. 2020

J Virol

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“…They were discovered, among others, in murine and human BM and are polyfunctional cytokine producers. These cells, being dependent on IL-15, reside in BM parenchyma ("chilling in the bone" [76]). They represent a pool of resident MTCs in close contact with the blood circulation and expandable upon peripheral or systemic antigen re-challenge [77].…”

Section: Tissue-resident Memory T Cells (T Mtcs)mentioning

confidence: 99%

New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection

Schirrmacher¹

2020

Biomedicines

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The topic is how to achieve long-term protective anti-tumor immunity by anti-cancer vaccination and what are its mechanisms. Cancer vaccines should instruct the immune system regarding relevant cancer targets and contain signals for innate immunity activation. Of central importance is T-cell mediated immunity and thus a detailed understanding of cognate interactions between tumor antigen (TA)-specific T cells and TA-presenting dendritic cells. Microbes and their associated molecular patterns initiate early inflammatory defense reactions that can contribute to the activation of antigen-presenting cells (APCs) and to costimulation of T cells. The concommitant stimulation of naive TA-specific CD4+ and CD8+ T cells with TAs and costimulatory signals occurs in T-APC clusters that generate effectors, such as cytotoxic T lymphocytes and T cell mediated immunological memory. Information about how such memory can be maintained over long times is updated. The role that the bone marrow with its specialized niches plays for the survival of memory T cells is emphasized. Examples are presented that demonstrate long-term protective anti-tumor immunity can be achieved by post-operative vaccination with autologous cancer vaccines that are modified by virus infection.

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High percentage of bone marrow CD8+ tissue-resident-like T cells predicts inferior survival in patients with acute myeloid leukemia

Cai,

Lai,

Yao

et al. 2024

Preprint

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Background Acute myeloid leukemia (AML) is a malignant clonal blood disease and the most common type of acute leukemia in adults. Despite continuous advances in treatments, the long-term prognosis of AML has not improved substantially. Tissue-resident memory T cells (TRMs) infiltrating solid tumors could influence tumor progression and the response to immune therapies; however, the proportion and prognostic significance of TRMs in the bone marrow (BM) of patients with AML are unclear. Methods We use flow cytometry to assay the phenotypic of 49 BM samples from patients newly diagnosed with AML (ND-AML). The Kaplan–Meier Plotter database verified the relationship between the expression of CD8+ TRM-like T cell characteristic genes (CD8A, CD69, and TOX) and patient survival. Additionally, to further explored the existence and function of TRM-like CD8+ T cells in the BM by analyzing the single cell proteo-genomic dataset of BM from AML and healthy. Results We found that the BM CD8+ effector memory (TEM) cells highly expressed CD69 (CD8+ TRM-like T cells), and their number significantly increased in ND-AML compared with that in HIs. The high CD8+ TRM-like subset is associated with poor overall survival. The Kaplan–Meier Plotter database verified that the survival rate of patients with high expression of CD8+ TRM-like T cell characteristic genes was significantly reduced, especially in the M4 and M5 subtypes. Phenotypic analysis revealed that the BM CD8+ TRM-like subpopulation exhibited exhausted T cell characteristics, but its high expression of CD27 and CD28 and low expression of CD57 suggest its high proliferative potential. The single-cell proteogenomic dataset confirmed the existence of TRM-like CD8+ T cells in the BM of AML and verified the high expression of immune checkpoints and costimulatory molecules. Conclusions We found that the accumulation of BM CD8+ TRM-like subset could be considered as an immune related survival prediction marker for patients with AML. Although the mechanisms of BM CD8+ TRM-like subset in driving immune escape in AML remains unknown, we believe that the targeted reversal of the function of this subset through immune checkpoint inhibitors and another immune-related “brake” may benefit the survival of some patients with AML.

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Tissue resident T cell memory or how the magnificent seven are chilling in the bone

Cited by 3 publications

References 34 publications

Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4⁺T_EMCells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice

Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4⁺T_EMCells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice

New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection

High percentage of bone marrow CD8+ tissue-resident-like T cells predicts inferior survival in patients with acute myeloid leukemia

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Tissue resident T cell memory or how the magnificent seven are chilling in the bone

Cited by 3 publications

References 34 publications

Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4+TEMCells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice

Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4+TEMCells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice

New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection

High percentage of bone marrow CD8+ tissue-resident-like T cells predicts inferior survival in patients with acute myeloid leukemia

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Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4⁺T_EMCells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice

Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4⁺T_EMCells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice