Role of TCRy& T cells in the mucosal response to intestinal infection

TCRy 的作用

• 批准号: 8281440
• 负责人: Leo Lefrancois
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281440
• 关键词: Adoptive Transfer; Affinity; Anatomy; Animal Model; Antigens; Automobile Driving; Binding; Cell Lineage; Cell Maintenance; Cells; Confocal Microscopy; Data; Dendritic Cells; Development; Disease; E-Cadherin; Epithelial Cells; Exhibits; Generations; HIV; Homeostasis; Human; Immune response; Immunity; In Situ; Infection; Infectious Agent; Ingestion; Interferons; Interleukin-15; Interleukin-17; Intestinal Mucosa; Intestines; Kinetics; Lamina Propria; Ligands; Listeria monocytogenes; Location; Memory; Mesentery; Movement; Mucosal Immunity; Mucous Membrane; Mus; Oral; Pathology; Physiological; Play; Population; Protein Binding; Proteins; Publishing; Recombinants; Role; Route; Signal Transduction; System; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Vaccines; Viral Tumor Antigens; Work; cell type; clinically relevant; cytokine; lymph nodes; oral infection; pathogen; receptor; response; two-photon

DESCRIPTION (provided by applicant): Despite the fact that clinically relevant infectious agents such as human immunodeficiency virus enter through the intestinal mucosa, the intestinal T cell response to infection remains understudied. Listeria monocytogenes (LM) has been used as a model organism for studying T cell responses and the normal route of infection for LM and a potential route for use of LM as a vaccine is through ingestion. Nevertheless, the vast majority of LM immunological studies utilize inoculation routes other than oral. Moreover in the bacterial strains used, the internalin A protein binds human E-cadherin with high affinity but poorly binds mouse E-cadherin. This receptor-ligand pairing is required for entry of LM into intestinal epithelial cells. The oral infection studies proposed here utilize a recombinant LM that expresses an internalin A protein with high affinity for mouse E-cadherin. Thus, the physiologic route and entry point of LM is recapitulated in our studies. Our preliminary studies revealed a remarkable mucosal TCRgd T cell response to oral LM infection, whose kinetics mimic an adaptive T cell response. Most importantly, this phenotypically and functionally distinct subset of mucosal TCRgd T cells are retained long-term and undergo a recall response upon challenge. The hypothesis to be tested in this proposal is that this specialized subset of putative memory TCRgd T cells is important for protection against LM infection and also regulates the long-term protective CDB TCRa¿ response. This hypothesis will be tested in the following specific aims: Aim 1. To test whether a subset of TCRgd represent bona fide mucosal memory cells. A detailed kinetic, phenotypic and functional analysis of the primary and secondary TCRgd cell response to oral LM infection will be undertaken. Aim 2. To determine the requirements for mucosal TCRgd activation in response to LM infection. Here we will test the role of dendritic cells, costimulation and cytokines in mounting primary and secondary TCRgd cell responses. Aim 3. To visualize the mucosal TCRgd cell response to oral LM infection. The oral infection system provides an exceptional opportunity to examine the anatomy of the mucosal TCRgd cell response.

描述（由申请方提供）：尽管临床相关感染因子（如人类免疫缺陷病毒）通过肠粘膜进入，但肠T细胞对感染的反应仍未得到充分研究。单核细胞增生李斯特菌（LM）已被用作研究T细胞反应和LM的正常感染途径的模式生物，LM作为疫苗的潜在途径是通过摄入。尽管如此，绝大多数LM免疫学研究采用口服以外的接种途径。此外，在所用的细菌菌株中，内化蛋白A蛋白以高亲和力结合人E-钙粘蛋白，但与小鼠E-钙粘蛋白结合较差。这种受体-配体配对是LM进入肠上皮细胞所必需的。本文提出的口腔感染研究利用重组LM，其表达对小鼠E-钙粘蛋白具有高亲和力的内化蛋白A蛋白。因此，LM的生理途径和进入点在我们的研究中被概括。我们的初步研究揭示了一个显着的粘膜TCRgd T细胞响应口腔LM感染，其动力学模拟适应性T细胞反应。最重要的是，粘膜TCRgd T细胞的这种表型和功能上不同的亚群被长期保留，并在攻击时经历回忆应答。在该提议中待检验的假设是，推定的记忆性TCRgd T细胞的该特化亚群对于保护免受LM感染是重要的，并且还调节长期保护性CDB TCR α反应。这一假设将在以下具体目标中得到检验：目标1。为了测试TCRgd的一个子集是否代表真正的粘膜记忆细胞。将对口服LM感染的原发性和继发性TCRgd细胞应答进行详细的动力学、表型和功能分析。目标2.确定LM感染时黏膜TCRgd激活的要求。在这里，我们将测试树突状细胞，共刺激和细胞因子在安装的主要和次要的TCRgd细胞反应的作用。目标3.观察粘膜TCRgd细胞对口腔LM感染的反应。口腔感染系统提供了一个特殊的机会来检查粘膜TCRgd细胞反应的解剖结构。