The Role of 4-1BB in T Cell and APC Interactions

项目负责人/主要研究者（最后一名、第一名、中间名）：Croft，Michael 2 R 01 AI 042944 - 10A 2 项目总结/摘要 4-1BB（CD 137）是TNFR超家族的成员，在许多炎症情况下强烈影响免疫细胞功能。4-1BB最初被描述为一种共刺激分子，与其已知的配体4-1BBL（TNF家族成员）结合，被认为可增强免疫应答和T细胞与APC之间的相互作用。然而，最近的数据表明，4-1BB生物学要复杂得多，并且4-1BB也可以在免疫应答期间发挥调节或负面作用。对于4- 1BB缺陷小鼠和使用不能表达4-1BB的T细胞，我们发现最初的作用，也许是其主要作用，是抑制作用而不是刺激作用。在基因缺陷动物中，4-1BB的缺乏会导致树突状细胞（DC）发育失调; T细胞对特定抗原的反应性增强;以及随着年龄的增长而出现的自发性炎症和自身免疫型症状。这些抑制活性的分子基础是未知的。我们已经发现，骨髓生成和DC分化的抑制是由于4-1BBL向骨髓祖细胞传递抑制信号。我们还假设，4-1BB信号传导到外周T细胞可以产生效应细胞和调节性T细胞，这取决于这些信号被接收的背景。本研究将研究4-1BB如何通过与4-1BBL的双向串扰发挥其调节作用，调节T细胞对抗原和造血的反应。我们将确定4-1BB与4-1BBL相互作用如何控制导致树突状细胞发育的髓系和单核细胞祖细胞，以及4-1BB和4-1BBL相互作用如何调节效应T细胞和调节T细胞之间的平衡，这可能有助于维持耐受性和预防自身免疫性疾病。

Program Director/Principal Investigator (Last, First, Middle): Croft, Michael 2 R01 AI042944-10A2 PROJECT SUMMARY/ABSTRACT 4-1BB (CD137), a member of the TNFR superfamily, strongly influences immune cell function in many inflammatory situations. 4-1BB was originally described as a costimulatory molecule and binding to its known ligand, 4-1BBL, a member of the TNF family, is thought to enhance immune responses and the cross-talk between T cells and APC. However, recent data have suggested that 4-1BB biology is much more complex, and that 4-1BB can also play a regulatory or negative role during immune responses. With 4-1BB-deficient mice and using T cells that cannot express 4-1BB, we have found that the initial role, and perhaps its primary role, is an inhibitory rather than stimulatory action. The absence of 4-1BB, in gene-deficient animals, leads to deregulated dendritic cell (DC) development; enhanced responsiveness of T cells to specific antigen; and spontaneous inflammation and autoimmune-type symptoms that develop with age. The molecular basis of these inhibitory activities are unknown. We have found that suppression of myelopoiesis and DC differentiation is due to 4-1BBL delivering inhibitory signals to bone marrow progenitor cells. We also hypothesize that 4-1BB signaling to peripheral T cells can generate both effector cells and regulatory T cells depending on the context in which these signals are received. The studies in this grant will investigate how 4-1BB exerts its modulatory actions through bidirectional cross-talk with 4-1BBL that regulate T cell responsiveness to antigen and hematopoiesis. We will determine how 4-1BB interacting with 4-1BBL controls myeloid and monocyte progenitors that lead to dendritic cell development, and how 4-1BB and 4-1BBL interactions modulate the balance between effector and regulatory T cells that may contribute to maintenance of tolerance and prevention of autoimmune disease.