B Cell Subsets as Antigen-presenting Cells in Peripheral Self-tolerance

描述（由申请人提供）：本研究的长期目标是鉴定诱导外周对自身抗原耐受的重要抗原呈递细胞（APC），重点是弱自身反应性B细胞亚群。B细胞对于结合在其抗原受体上的抗原是特别有效的APC，因此在胸腺和外周，自反应性B细胞可能比传统的耐受性APC更有效地呈递自身抗原。为了避免致病性T细胞和B细胞相互激活的恶性循环中的正反馈，在这些T细胞被感染激活之前，自身反应性B细胞可能需要诱导辅助性T细胞对它们识别并有效呈现的自身抗原产生耐受性。众所周知，B细胞亚群在募集T细胞帮助的能力和分泌自身抗体的倾向方面存在很大差异，但它们在诱导初始CD4 T细胞耐受的能力方面尚未进行比较。自反应性B细胞的三个亚群可能特别重要，作为CD4 T细胞的耐受性APC。其中一个亚群是短命的、无能的、未成熟的移行性B细胞，它们被保留在T细胞区域，由于它们的抗原受体被自身抗原参与，它们不能进入寿命较长的B细胞区室。另一种是自我更新的边缘区B细胞，它们被自身抗原选择到这个特殊的B细胞亚群中，并准备好对血源性病原体做出快速的抗体反应。第三种是自我更新的B-1 B细胞，在早期发育中被播种到外周，通过自身抗原反应性被选择和维持，并产生种系编码的天然和不依赖t的抗体，以防止细菌感染。该项目的目的是首次确定B细胞亚群在健康淋巴器官中稳定状态下自然位置的抗原呈递和耐受诱导的内在效率，使用一种独特的转基因动物模型，其中抗原呈递可以限制在某些亚群的B细胞中。拟议的实验还将测试缺乏特定B细胞亚群的动物是否缺乏CD4 T细胞对这些B细胞呈递的自身抗原的耐受性。

DESCRIPTION (provided by applicant): The long-range goal of this research is to identify the significant antigen presenting cells (APC) that induce peripheral tolerance to self antigens, with a focus on weakly autoreactive B cell subsets. B cells are particularly efficient APC for antigens bound to their antigen receptors, so self-reactive B cells may present self-antigens more efficiently than conventional tolerizing APC in the thymus and periphery. To avoid positive feedback in a vicious cycle of mutual activation by pathogenic T and B cells, it may be necessary for autoreactive B cells to induce helper T cell tolerance to those self-antigens that they recognize and present efficiently, before those T cells are activated by infections. It is known that B cell subsets differ substantially from one another in their ability to recruit T cell help and their propensity to secrete autoantibodies, but they have not been compared with regard to their ability to induce tolerance in naive CD4 T cells. Three subsets of self-reactive B cells may be particularly important as tolerogenic APC for CD4 T cells. One subset is the short-lived, anergic, immature transitional B cells that are retained in T cell areas and fail to enter the longlived B cell compartments because their antigen receptors are engaged by self-antigens. Another is the self-renewing marginal zone B cells that are selected into this special B cell subset by self antigens, and are poised for a rapid antibody response to blood-borne pathogens. The third is the self-renewing B-1 B cells that are seeded to the periphery in early development, are selected and sustained by self-antigen reactivity, and produce germline-encoded, natural and T-independent antibodies that protect against bacterial infections. The objective of this project is to determine for the first time the intrinsic efficiency of antigen presentation and tolerance induction by B cell subsets in their natural locations in the steady state in healthy lymphoid organs, using a unique transgenic animal model in which antigen presentation can be limited to B cells of certain subsets. The proposed experiments will also test whether animals deficient in particular B cell subsets are deficient in CD4 T cell tolerance to self-antigens presented by those B cells. Relevance: The failure of self-tolerance underlies autoimmune disease. This application investigates the mechanisms that maintain self-tolerance while allowing a vigorous response to infections. Understanding mechanisms of immunological tolerance may lead to new interventions for prevention or cure of autoimmune diseases, such as lupus erythematosus, rheumatoid arthritis, and diabetes. New methods to induce immunological tolerance will also have important applications in organ and tissue transplantation, gene therapy, and treatment of chronic infections.