Tolerogenic Interactions of 4-1BB

4-1BB 的耐受性相互作用

• 批准号: 7771080
• 负责人: Michael Croft
• 金额: $ 23.61万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-10 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7771080
• 关键词: Accounting; Age; Animals; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biology; Cancerous; Cell division; Cell surface; Cells; Cessation of life; Characteristics; Chronic; Data; Dendritic Cells; Development; Disease; Failure; Family; Galactose Binding Lectin; Galectin 3; Genes; Goals; Grant; Hematopoiesis; Immune; Immune response; Immune system; Immunity; Induction of Apoptosis; Inflammation; Knowledge; Lead; Ligands; Ligation; Mature T-Lymphocyte; Mediating; Molecular; Mus; Nature; Phenotype; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Signal Transduction; Surface; Symptoms; T cell response; T-Lymphocyte; TNF gene; Testing; Tumor Necrosis Factor Receptor; base; member; novel; pathogen; public health relevance; receptor; response

DESCRIPTION (provided by applicant): The failure of T cell tolerance can lead to spontaneous inflammation and at worst autoimmune disease. The control of T cell tolerance versus immunity in part relies on signals from co-stimulatory and co-inhibitory receptors that control various activities of T cells. 4-1BB (CD137, ILA, TNFRSF9), a member of the tumor-necrosis factor receptor (TNFR) super-family, was originally identified as an inducible co-stimulatory molecule on activated T cells. The ligand of 4-1BB (4-1BBL, TNFSF9), a member of the TNF super-family, expressed on activated APC binds to 4-1BB that is induced on T cells, generating positive signals inside T cells to help them function and to augment various aspects of immunity. In contrast we have found an inhibitory role for 4-1BB that does not rely on interaction with 4-1BBL. The absence of 4-1BB, in gene-deficient animals, leads to an enhanced rather than suppressed responsiveness of T cells to specific antigen, and 4-1BB-deficient mice spontaneously generate autoimmune-type phenotypes with chronic inflammation at the mucosal interfaces, a phenotype not seen in 4-1BBL-deficient mice. Our hypothesis is that 4-1BB binds with unidentified ligands that are constitutively expressed or induced early in an immune response to limit T cell reactivity and maintain tolerance, but by switching partners to 4-1BBL expressed later with inflammation, 4-1BB can then provide a positive stimulatory action. Our preliminary results have identified both galectin-3 and galectin-9, two reported suppressive molecules, as partners for 4- 1BB. The studies in this grant will investigate the interaction of galectins with 4-1BB and determine whether 4-1BB/galectin interactions account for 4-1BB negatively regulating T cell responsiveness. The identification and characterization of novel binding partners for 4-1BB will provide new understanding into 4-1BB biology as well as T cell tolerance and chronic inflammation. PUBLIC HEALTH RELEVANCE: 4-1BB and its ligand(s) are expressed on the surface of many immune cells and are thought to regulate the ability to mount an immune response. 4-1BB provides essential signals to a T cell to allow it to continue dividing late in its response, and to suppress excessive death. However, 4-1BB interactions also act as a rate-limiting step to control initial T cell division and expansion. By understanding where and when 4-1BB and its ligand(s) are expressed, and the functional importance of these putative interactions, we will gain knowledge that might lead to ways to either enhance or suppress T cell responses, and so might be therapeutically relevant in a number of disease settings such as in limiting autoimmunity, or augmenting the ability to respond to cancerous cells or infectious pathogens.

描述（由申请人提供）：T细胞耐受性的失败可导致自发性炎症，最严重的是自身免疫性疾病。T细胞耐受性相对于免疫性的控制部分依赖于来自控制T细胞的各种活性的共刺激和共抑制受体的信号。4-1BB（CD 137，ILA，TNFRSF 9）是肿瘤坏死因子受体（TNFR）超家族的成员，最初被鉴定为活化T细胞上的可诱导共刺激分子。4-1BB（4-1BBL，TNFSF 9）的配体是TNF超家族的一员，在活化的APC上表达，与T细胞上诱导的4-1BB结合，在T细胞内产生阳性信号，以帮助它们发挥功能并增强免疫力的各个方面。相反，我们发现4-1BB的抑制作用不依赖于与4-1BBL的相互作用。在基因缺陷动物中，4-1BB的缺失导致T细胞对特异性抗原的反应性增强而不是抑制，并且4- 1BB缺陷小鼠自发地产生自身免疫型表型，在粘膜界面处具有慢性炎症，这是在4- 1BBL缺陷小鼠中未观察到的表型。我们的假设是，4-1BB与未鉴定的配体结合，这些配体在免疫应答早期组成性表达或诱导，以限制T细胞反应性并维持耐受性，但通过将伴侣转换为随后在炎症中表达的4-1BBL，4-1BB可以提供积极的刺激作用。我们的初步结果已经确定了半乳糖凝集素-3和半乳糖凝集素-9，两个报告的抑制分子，作为合作伙伴的4- 1BB。这项研究将调查半乳糖凝集素与4-1BB的相互作用，并确定4-1BB/半乳糖凝集素相互作用是否导致4-1BB负调节T细胞反应性。4-1BB的新结合伴侣的鉴定和表征将为4-1BB生物学以及T细胞耐受和慢性炎症提供新的理解。 公共卫生相关性：4-1BB及其配体在许多免疫细胞的表面上表达，并且被认为调节产生免疫应答的能力。4-1BB为T细胞提供必要的信号，使其在反应后期继续分裂，并抑制过度死亡。然而，4-1BB相互作用也是控制初始T细胞分裂和扩增的限速步骤。通过了解4-1BB及其配体在何处和何时表达，以及这些假定相互作用的功能重要性，我们将获得可能导致增强或抑制T细胞应答的方法的知识，因此可能在许多疾病环境中具有治疗相关性，例如限制自身免疫，或增强对癌细胞或感染性病原体的应答能力。

项目成果

Regulatory T Cell-Mediated Suppression of Inflammation Induced by DR3 Signaling Is Dependent on Galectin-9.

• DOI: 10.4049/jimmunol.1700575
• 发表时间: 2017-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Madireddi S;Eun SY;Mehta AK;Birta A;Zajonc DM;Niki T;Hirashima M;Podack ER;Schreiber TH;Croft M
• 通讯作者: Croft M