Cutaneous pathogen-specific tissue resident memory T cells in human aging

人类衰老过程中皮肤病原体特异性组织常驻记忆 T 细胞

• 批准号: 10624283
• 负责人: David M Koelle
• 金额: $ 55.87万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624283
• 关键词: Abbreviations; Adult; Age; Aging; Animals; Antigens; Biological Assay; Biopsy; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Mobility; Cells; Chronic; Clinical; Contralateral; Cranial Nerves; Cutaneous; Data; Deposition; Elderly; Exanthema; Focal Infection; Ganglia; Gene Expression Profile; Genetic Transcription; Herpes Simplex Infections; Herpes zoster disease; Herpesvirus Type 3; Home; Homing; Host Defense; Human; Immune; Immunity; Immunology; Infection; Intramuscular; Intramuscular Injections; Licensing; Life; Malignant Neoplasms; Measurement; Measures; Mediating; Memory; Metabolic; Methods; Microbe; Molecular Profiling; Morbidity - disease rate; Mus; Mutation; National Institute of Allergy and Infectious Disease; National Institute of Dental and Craniofacial Research; Natural Immunity; Neurons; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Physiological; Population; Positioning Attribute; Predisposition; Prevention; Primary Infection; Proliferating; Proteins; RNA; Recovery; Rejuvenation; Research; Risk; Risk Factors; Route; Simplexvirus; Site; Skin; Skin Cancer; Special Population; Specificity; Subgroup; T cell response; T-Lymphocyte; Time; Tissues; Twin Multiple Birth; VZV vaccine; Vaccination; Vaccines; Viral; Virus; Virus Diseases; acquired immunity; age effect; age related; aged; circulating biomarkers; craniofacial; effector T cell; healing; improved; interest; mRNA Expression; mortality; neoantigens; pathogen; permissiveness; prevent; recurrent infection; senescence; tissue resident memory T cell; tool; vaccine delivery; vaccine development; vaccine discovery; vaccinology

Project Summary: The waning of immunity has a major impact on morbidity and mortality in the aged. Antigen-specific, acquired, and especially T-cellular is important in host defense against chronic intracellular pathogens and cancer. Infections with these microbes and skin cancers with high mutational burdens and neoepitope loads, are disproportionally high in the elderly. In this application, the investigative team uses an established tetramer and TCR toolkit for the study of T-cell responses to varicella zoster virus infections (VZV) in humans to determine the mechanisms of age-related susceptibility to shingles, and the mechanisms of action of a uniquely successful vaccine that retains efficacy in the elderly. Recently, it has been appreciated that host defense against many localized infections is mediated by special populations of tissue resident memory cells, abbreviated TRM. As murine and human studies have advanced, the lineage of TRM, TRM subsets, and the transcriptional and metabolic signature of TRM in various tissues have begun to come into focus. TRM are locally mobile, patrol tissue for antigen, and can proliferate upon antigen re-exposure, yet do not re-enter the blood and are out of reach of blood-based studies. Notably, studies of human antigen-specific TRM are rare, such that assays of overall TRM populations may overlook the complexity of TRM. Here, we use VZV infection and vaccination as related probes of TRM T-cells across the age spectrum. Aim 1 focuses on endogenous reactivation of VZV and uses biopsies of healed shingles and control skin to, for the first time, fully characterize helpful human virus-specific TRM at the single cell level. Aim 2 uses the new RZV vaccine for shingles prevention, which retains efficacy even in aged adults, to determine if the vaccine leads to TRM seeding in the skin, improvement in the pool of homing-committed cells in the blood, or both. Taken together, these studies will increase our understanding of age- related changes in vital effector T-cells and strategies that may be useful to overcome immune senescence.

项目总结:

项目成果

BTK inhibitors impair humoral and cellular responses to recombinant zoster vaccine in CLL.

• DOI: 10.1182/bloodadvances.2021006574
• 发表时间: 2022-03-22
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Pleyer C;Laing KJ;Ali MA;McClurkan CL;Soto S;Ahn IE;Nierman P;Maddux E;Lotter J;Superata J;Tian X;Wiestner A;Cohen JI;Koelle DM;Sun C
• 通讯作者: Sun C

Selective retention of virus-specific tissue-resident T cells in healed skin after recovery from herpes zoster.

• DOI: 10.1038/s41467-022-34698-4
• 发表时间: 2022-11-15
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Laing, Kerry J.;Ouwendijk, Werner J. D.;Campbell, Victoria L.;McClurkan, Christopher L.;Mortazavi, Shahin;Waters, Michael Elder;Krist, Maxwell P.;Tu, Richard;Nguyen, Nhi;Basu, Krithi;Miao, Congrong;Schmid, D. Scott;Johnston, Christine;Verjans, Georges M. G. M.;Koelle, David M.
• 通讯作者: Koelle, David M.