Antigen Processing And Presentation In The Intestine

抗原在肠道中的加工和呈现

• 批准号: 6521434
• 负责人: BRIAN KELSALL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6521434
• 关键词: MHC class I antigen; MHC class II antigen; Peyer's patches; T lymphocyte; antigen presentation; cell differentiation; cholera toxin; cytokine; dendritic cells; flow cytometry; intestines; laboratory mouse; mucosal immunity; oral tolerance; polymerase chain reaction

This project focuses on how antigens are processed in the intestine of mice. While it is clear that the outcome of oral antigen exposure can be either positive, i.e., the development of mucosal IgA responses, and in some cases the induction of systemic immunity as well, or negative, i.e., the induction of oral tolerance, the details of why one or the other outcome occurs is complex and poorly understood. While it is known that the antigen formulation, the presence of adjuvants, and the antigen dose, as well as genetic factors, can affect mucosal immune responses, how these act to influence immunity has never been established. In prior studies we have established the presence of different antigen-presenting cell populations in the Peyer's patch (PP) and lamina propria. Over the past year we have detailed the surface phenotype, function, and migration of DCs in the PP using in situ immunofluorecense microscopy and in situ hybridization, flow cytometry of purified cells, and in vitro assays of cytokine production (ELISA and quantitative RT-PCR) and T cell differentiation. We determined that there are 3 separate subpopulations of immature DCs in the PP, lymphoid (CD8+), myeloid (CD11b+), and double negative (DN) Dcs that express neither CD8 or CD11b. These separated DC subpopulations are located in distinct sites in the PP, and are capable of inducing the differentiaion of T cells into cells that produce unique cytokine profiles. Most importantly, we demonstrated that PP DCs have the unique capacity to induce the differntiation of T cells that produce high levels of IL-10, a cytokine important for the IgA B cell differentiation. These studies thus are some of the first to directly demonstrate that DCs from different tissues may be unique in their ability to induce tissue specific immunity.

这个项目的重点是抗原是如何在小鼠的肠道中处理的。虽然很明显，口服抗原暴露的结果可以是积极的，即发展粘膜IgA反应，在某些情况下还可以诱导全身免疫，也可以是消极的，即诱导口服耐受，但为什么会发生一种或另一种结果的细节是复杂的，人们对此知之甚少。虽然已知抗原配方、佐剂的存在、抗原剂量以及遗传因素都可以影响粘膜免疫反应，但这些因素如何影响免疫一直没有得到证实。在先前的研究中，我们已经确定了不同的抗原提呈细胞群存在于Peyer氏斑(PP)和固有层。在过去的一年里，我们利用原位免疫荧光显微镜和原位杂交，纯化细胞的流式细胞术，以及细胞因子产生(ELISA和定量RT-PCR)和T细胞分化的体外检测，详细地研究了PP中DC的表面表型、功能和迁移。我们确定在PP、淋巴系(CD8+)、髓系(CD11b+)和双阴性(DN)DC中有3个独立的未成熟DC亚群，既不表达CD8也不表达CD11b。这些分离的DC亚群位于PP的不同位置，能够诱导T细胞分化为产生独特细胞因子谱的细胞。最重要的是，我们证明了PP DC具有独特的诱导T细胞分化的能力，这些T细胞产生高水平的IL-10，这是一种对IgA B细胞分化至关重要的细胞因子。因此，这些研究首次直接证明了来自不同组织的DC诱导组织特异性免疫的能力可能是独一无二的。