Tolerogenic Interactions of 4-1BB

描述(由申请人提供)：T细胞耐受失败可导致自发性炎症，在最糟糕的情况下会导致自身免疫性疾病。T细胞耐受与免疫的控制在一定程度上依赖于控制T细胞各种活动的共刺激和共抑制受体的信号。4-1BB(CD137，ILA，TNFRSF9)是肿瘤坏死因子受体(TNFR)超家族的成员，最初被发现是活化T细胞上的一种可诱导的共刺激分子。肿瘤坏死因子超家族成员4-1BB(4-1BBL，TNFSF9)的配体表达于活化的APC上，与T细胞诱导的4-1BB结合，在T细胞内产生阳性信号，帮助T细胞发挥功能，增强免疫功能。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。在基因缺陷的动物中，4-1BB的缺失导致T细胞对特定抗原的反应性增强而不是被抑制，4-1BB缺陷的小鼠自发产生自身免疫型表型，并在粘膜界面发生慢性炎症，这种表型在4-1BBL缺陷的小鼠中看不到。我们的假设是，4-1BB与免疫反应早期结构性表达或诱导的未知配体结合，以限制T细胞的反应性并维持耐受性，但通过将伴侣切换到后来因炎症表达的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Galectin-3和Galectin-9这两个已知的抑制分子都是4-1BB的合作伙伴。这项研究将调查Galectins与4-1BB的相互作用，并确定4-1BB/Galectin相互作用是否导致4-1BB对T细胞反应性的负面调节。4-1BB新的结合伙伴的鉴定和鉴定将为理解4-1BB的生物学以及T细胞耐受和慢性炎症提供新的认识。 公共卫生相关性：4-1BB及其配体(S)表达在许多免疫细胞的表面，被认为调节启动免疫反应的能力。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的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(S)在何时何地表达，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细胞反应的方法的知识，因此可能在许多疾病环境中具有治疗意义，如限制自身免疫，或增强对癌细胞或传染性病原体的反应能力。

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.