(BOYSON): MOLECULAR DETERMINANTS OF NKT CELL ACTIVATION BY CD1D AND ITS LIGANDS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 * 请注意：Boyson博士于2008年10月1日从COBRE“毕业”。 他现在是Jason Botten博士的导师。 不变的自然杀伤T（iNKT）细胞包括对感染性疾病、自身免疫、耐受诱导和肿瘤免疫学具有深远影响的新型T细胞亚群。NKT细胞可以通过识别由CD 1d呈递的微生物源糖脂（直接途径）或通过TLR配体激活的抗原呈递细胞产生的IL-12和IL-18（间接途径）来激活。在活化后，NKT细胞迅速分泌大量的多种细胞因子并活化其它白细胞亚群，例如树突细胞、巨噬细胞、B细胞和自然杀伤细胞。鉴于它们在肠道、肝脏和肺中的相对高频率，这些观察结果表明NKT细胞可能在免疫反应的早期事件中发挥作用。 在此资助期间，我们将注意力集中在研究NKT细胞功能的遗传决定因素上。我们已经发表了观察结果，即在不同的遗传背景中，NKT细胞的数量和功能存在广泛的差异。这些菌株依赖性差异与显著的生理效应相关，例如对aGalCer诱导的气道高反应性（哮喘的主要特征）、aGalCer诱导的肝损伤和aGalCer诱导的妊娠丢失的共同易感性。 我们现在已经通过研究NKT细胞数量和功能的应变依赖性变化的意义来扩展这项工作。我们已经发现，表现出低NKT细胞数量和功能的菌株，如129 S1/SvImJ，在体内对LPS的反应很差。我们还发现，肝脏NKT细胞的数量是严格控制的SLAM/CD 2基因座1号染色体上，具有许多菌株之间的多态性。最令人感兴趣的是，我们已经发现，使用其中129 S1/SvImJ SLAM/CD 2基因座渗入到C57 BL/6 J背景上的同类菌株，除了控制肝NKT细胞数量之外，SLAM/CD 2基因座还控制对LPS的体内应答。总之，我们的数据表明，SLAM依赖性控制NKT细胞数量调节体内TLR配体的反应。我们目前正在准备一份提交的手稿。 2008年出版物： Rymarchyk，S.L.，H. Lowenstein，J. Mayette，S.R. Foster，D.丹比，I.W.豪岛阿克坦河Meyer，M.E. Poynter和J.E.博伊森2008. NKT细胞数量和功能的广泛自然变异。免疫学125：331-343。 埃克斯利，硕士，R. Hou，黑腹滨藜A. Shaulov，E. Tonti，P. Dellabona，G.卡索拉蒂岛阿克巴里阁下Akman，E.A.格林菲尔德，J.E. Gumperz，J.E. Boyson，S.P. Balk和S.B.威尔逊2008.用TCR α链CDR 3环特异性单克隆抗体选择性激活、扩增和监测人iNKT细胞。European Journal of Immunology 38（6）：1756-1766. J.E.博伊森岛Aktan，D. Barkhuff和A.吟唱母胎界面的NKT细胞。2008.免疫学研究37：565-582。 小奥尔森，C.M.，T.C.贝茨，H。Izadi，J.D. Radolf，S.A. Huber，J.E. Boyson和J. Anguita。2009.恒定自然杀伤T细胞对干扰素γ的局部调节急性莱姆病性心脏炎Journal of Immunology 182（6）：p. 3728-3734. Paveglio，S，J. Allard，S. Foster，J. Ather，M. Bevelander，J. Mayette，L. Whittaker，J.E.博伊森和法医波因特IDO在小鼠气道上皮细胞内的过表达减轻了烟曲霉抗原暴露期间的CD 4 + T细胞活性（提交）。 指导总结： Elizabeth A. Bonney，医学博士 作为佛蒙特州免疫学和传染病中心的COBRE成员，我与COBRE内的几个级别的学员有指导关系，包括研究生和博士后研究员。 我担任乔恩·博伊森的导师，他在2008年6月“毕业”到高级教师的水平，目前是杰森·博滕的导师。 乔恩和我继续在与异常妊娠的生物学相关的问题上合作。 我将继续在划定和实现长期职业目标方面提供支持。 我们继续大约每两个月举行一次会议。 Jason和我合作使用小鼠模型更好地了解淋巴细胞性脉络丛脑膜炎病毒感染的免疫生物学，特别是因为它与组织特异性免疫有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ***Please note: Dr. Boyson "graduated" off the COBRE as of 10/1/2008. He now serves as a mentor for Dr. Jason Botten. Invariant natural killer T (iNKT) cells comprise a novel subset of T cells that has a profound effect on infectious disease, autoimmunity, tolerance induction, and tumor immunology. NKT cells can be activated through recognition of microorganism-derived glycolipids presented by CD1d (direct pathway), or through IL-12 and IL-18 produced by antigen presenting cells activated by TLR ligands (indirect pathway). Upon activation, NKT cells rapidly secrete large amounts of a wide variety of cytokines and activate other leukocyte subsets such as dendritic cells, macrophages, B cells, and natural killer cells. Given their relatively high frequency in the gut, liver, and lung, these observations suggest that NKT cells may play a role in early events of a developing immune response. During this funding period, we have focused our attention on investigation of genetic determinants of NKT cell function. We have published the observation that there is widespread variation in NKT cell number and function among different genetic backgrounds. These strain-dependent differences are correlated with significant physiological effects such as shared susceptibility to aGalCer-induced airway hyperreactivity (a cardinal feature of asthma), aGalCer-induced liver injury, and aGalCer-induced pregnancy loss. We have now extended this work by investigating the significance of strain-dependent variation in NKT cell number and function. We have found that strains exhibiting low NKT cell number and function, such as 129S1/SvImJ, respond poorly in vivo to LPS. We have also found that liver NKT cell number is under strictly controlled by the SLAM/CD2 locus on chromosome 1 which possesses numerous polymorphisms between strains. Most interesting, we have found using a congenic strain where the 129S1/SvImJ SLAM/CD2 locus was introgressed onto the C57BL/6J background that, in addition to controlling liver NKT cell number, the SLAM/CD2 locus controls the in vivo response to LPS. Taken together, our data suggest that SLAM-dependent control of NKT cell number modulates the in vivo response to TLR ligands. We are currently preparing a manuscript for submission. Publications 2008: Rymarchyk, S.L., H. Lowenstein, J. Mayette, S.R. Foster, D. Damby, I.W. Howe, I. Aktan, R.E. Meyer, M.E. Poynter, and J.E. Boyson. 2008. Widespread natural variation in NKT cell number and function. Immunology 125:331-343. Exley, M.A., R. Hou, A. Shaulov, E. Tonti, P. Dellabona, G. Casorati, O. Akbari, H.O. Akman, E.A. Greenfield, J.E. Gumperz, J.E. Boyson, S.P. Balk, and S.B. Wilson. 2008. Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR alpha-chain CDR3 loop. European Journal of Immunology 38(6):1756-1766. J.E. Boyson, I. Aktan, D. Barkhuff, and A. Chant. NKT cells at the maternal-fetal interface. 2008. Immunological Investigations 37:565-582. Olson Jr., C.M., T.C. Bates, H. Izadi, J.D. Radolf, S.A. Huber, J.E. Boyson, and J. Anguita. 2009. Local regulation of interferon gamma by invariant natural killer T cells modulates acute lyme carditis. Journal of Immunology 182(6): p. 3728-3734. Paveglio, S, J. Allard, S. Foster, J. Ather, M. Bevelander, J. Mayette, L. Whittaker, J.E. Boyson, and M.E. Poynter. Overexpression of IDO within mouse airway epithelial cells mitigates CD4+ T-cell activities during Aspergillus fumigatus antigen exposure (submitted). Mentoring Summaries: Elizabeth A. Bonney, M.D. As a member of the COBRE for the Vermont Center for Immunology and Infectious disease I have mentoring relationships with several levels of trainees within the COBRE, including graduate students and post doctoral fellows. I served as the mentor for Jon Boyson, who, as of June 2008 "graduated " to the level of Senior Faculty, and who currently mentors Jason Botten. Jon and I continue to collaborate on issues related to biology of abnormal pregnancy. I continue to offer support in terms of delineation and achievement of long-term career goals. We continue to meet approximately once every two months. Jason and I collaborate on using a mouse model better understand the immunobiology of infection with Lymphocytic choriomeningitis virus, particularly as it relates to tissue-specific immunity.