B1B lymphocytes generate T cell-independent memory

描述（由申请人提供）：在美国，压倒性菌血症是传染病死亡的主要原因之一。防止菌血症演变为危及生命的感染的一个关键因素是宿主迅速产生针对入侵病原体的保护性抗体的能力。T细胞非依赖性（TI）应答具有高度保护性，并且比T细胞依赖性（TD）应答显著更快地发展。然而，T1应答长期以来一直被认为仅仅是短暂的并且不能赋予持久的保护。回归热细菌疏螺旋体（Borrelia hermsii）在血液中生长至极高浓度，但以T1方式迅速清除。我们利用了B的小鼠模型。hermsii感染，以表明这种T1应答实际上产生长期保护。这种免疫力是由B1 B淋巴细胞赋予的，B1 B淋巴细胞是B细胞的一个新的亚群，其功能尚未完全了解。这些B1 B细胞在B消退的同时扩增。hermsii感染，持续存在，并分泌保护性IgM。有趣的是，虽然来自恢复期小鼠的B1b细胞在转移到免疫缺陷小鼠时具有完全的保护作用，但幼稚B1b细胞仅提供部分和短暂的免疫力，这表明恢复期B1b细胞显然具有免疫记忆。为了理解这种T1记忆样应答的基础，并鉴定B1 B细胞靶向的特异性抗原，将解决以下问题：（1）什么是B。hermsii抗原被保护性B1b衍生的IgM识别？IgM单克隆抗体（mAb）将由来自恢复期B1 B细胞和B的杂交瘤产生。将鉴定由这些IgM mAb识别的hermsii抗原，并且还将测试mAb在体外杀死该细菌和在体内保护小鼠的能力。(2)B的频率和保护能力是多少。hermsii特异性B1b细胞的幼稚和恢复期小鼠？将通过流式细胞术和ELISPOT和VH CDR 3光谱分析确定频率。(3)恢复期小鼠和未处理小鼠的抗原特异性B1b细胞之间的内在差异是什么？细胞对各种刺激的增殖动力学和响应于B分化为抗体分泌细胞。将在体外和体内评估Hermsii。了解B1b细胞赋予的T1保护性应答的寿命的基础将提供产生针对表达T1抗原的病原体的有效疫苗的新方法。

DESCRIPTION (provided by applicant): Overwhelming bacteremia is one of the leading causes of death by infectious disease in the United States. A critical factor in preventing bacteremia from evolving into a life-threatening infection is the ability of the host to rapidly generate protective antibodies against the invading pathogens. T cell-independent (Tl) responses are highly protective and develop significantly more rapidly than T cell-dependent (TD) responses. However, Tl responses have been long considered exclusively short-lived and incapable of conferring long-lasting protection. The relapsing fever bacterium Borrelia hermsii grows to exceedingly high concentrations in the blood, but is rapidly cleared in a Tl manner. We have utilized a murine model of B. hermsii infection to show that this Tl response in fact generates long-term protection. This immunity is conferred by B1b lymphocytes, a novel subset of B cells whose functions are not yet well understood. These B1b cells expand concurrent with the resolution of B. hermsii infection, persist, and secrete protective IgM. Interestingly, while B1b cells from convalescent mice confer complete protection when transferred to immunodeficient mice, naive B1b cells provide only partial and short-lived immunity, indicating that the convalescent B1b cells have apparently acquired immunological memory. To understand the basis of this Tl memory-like response, and to identify the specific antigen(s) targeted by B1b cells, the following questions will be addressed: (1) What B. hermsii antigens are recognized by protective B1b-derived IgM? IgM monoclonal antibodies (mAbs) will be generated from hybridomas derived from convalescent B1b cells and the B. hermsii antigens recognized by those IgM mAbs will be identified and mAbs will also be tested for the ability to kill this bacterium in vitro and protect mice in vivo. (2) What is the frequency and protective capability of B. hermsii-specific B1b cells of naive and convalescent mice? Frequencies will be determined by flow cytometry and ELISPOT and VH CDR3 spectratyping. (3) What are the intrinsic differences between antigen-specific B1b cells of convalescent and naive mice? Kinetics of cell proliferation to a variety of stimuli and differentiation into antibody-secreting cells in response to B. hermsii will be assessed in vitro and in vivo. Understanding the basis for the longevity of the Tl protective responses conferred by B1b cells will provide novel approaches to generate effective vaccines against pathogens expressing Tl antigens.