Activating Alloreactive T Cells

激活同种反应性 T 细胞

• 批准号: 6690043
• 负责人: John J Iacomini
• 金额: $ 32.78万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690043
• 关键词: Activating; Alloreactive; Cells

DESCRIPTION (provided by applicant): T cells recognize allogeneic major histocompatibility (MHC) antigens via two distinct pathways of antigen presentation. The direct pathway involves the recognition of intact allogeneic MHC molecules on the surface of donor cells by host T cells, whereas the indirect pathway involves the recognition of donor MHC-derived peptides that are processed by host antigen presenting cells (APCs) and presented as peptides to T cells. CD4 T cells that recognize allogeneic antigens through the indirect pathway play a major role in allograft rejection, yet the requirements for activating CD4 T cells through the indirect pathway remain undefined. We observed that in CD8 T cell depleted and thymectomized mice, CD4 T cell mediated rejection of MHC class I disparate skin allografts was associated with expression of interleukin-4 (IL-4). In vivo, a deficiency in IL-4 production inhibited the activation of alloreactive IL-2-, IL-4-, and IFN-g-producing CD4 T cells in mice challenged with allogeneic skin grafts, resulting in prolongation of skin graft survival. Inhibition of IL-4 during mixed allogeneic lymphocyte cultures prevented the up-regulation of the co-stimulatory molecules CD80 and CD86 on APCs, and resulted in a defect in the ability of APCs to generate sufficient signals for activation of alloreactive T cells. Thus, production of IL-4 is critical for the activation and expansion of CD4 T cells that recognize alloantigen through the indirect pathway. The specific aims are to: 1) Determine the source of IL-4 production during the response to allografts in vivo; 2) Determine the conditions in which IL-4 is required for CD4 T cell activation; 3) Determine how IL-4 affects APC maturation, function and the ability to stimulate alloreactive CD4 effector T cells; and 4) Determine the stage at which IL-4 neutralization prevents acquisition of CD4 T cell effector function. The studies described in this proposal will advance our understanding of mechanisms leading to alloreactive T cell activation and advance our understanding of fundamental aspects of T cell biology. In addition the proposed studies may lead to significant advances in clinical transplantation.

描述（由申请人提供）：T细胞通过抗原表现的两种不同的途径识别同种异性主要组织相容性（MHC）抗原。直接途径涉及通过宿主T细胞对供体细胞表面上完整的同种异体MHC分子的识别，而间接途径涉及识别由供体MHC衍生的肽通过宿主抗原呈现细胞（APC）处理的供体MHC衍生的肽，并将其作为T细胞的肽表现为T细胞。通过间接途径识别同种异体抗原的CD4 T细胞在同种异体移植排斥中起主要作用，但是通过间接途径激活CD4 T细胞的要求仍然不确定。我们观察到，在CD8 T细胞耗尽和胸腺切除小鼠中，CD4 T细胞介导的MHC I类脱离皮肤同种异体的排斥反应与白介素-4的表达有关（IL-4）。在体内，IL-4产生的缺乏抑制了同种异体皮肤移植物质疑的小鼠中产生的同种异体IL-2-，IL-4-和产生IFN-G的CD4 T细胞的激活，从而导致皮肤移植物存活率延长。混合异源淋巴细胞培养过程中IL-4的抑制作用阻止了APC上的共刺激分子CD80和CD86的上调，并导致APC产生足够信号以激活全反性T细胞的能力。因此，IL-4的产生对于通过间接途径识别同源抗原的CD4 T细胞的激活和扩展至关重要。具体目的是：1）确定对体内同种异体移植反应期间IL-4产生的来源； 2）确定CD4 T细胞激活需要IL-4的条件； 3）确定IL-4如何影响APC成熟，功能和刺激同种反应性CD4效应T细胞的能力； 4）确定IL-4中和阻止CD4 T细胞效应函数的获取的阶段。该提案中描述的研究将促进我们对导致同种反应性T细胞激活的机制的理解，并提高我们对T细胞生物学基本方面的理解。此外，提出的研究可能会导致临床移植的重大进展。