MECHANISMS OF T LYMPHOCYTE MIGRATION INTO SKIN

T 淋巴细胞迁移至皮肤的机制

• 批准号: 2517465
• 负责人: RICHARD N TAMURA
• 金额: $ 17.16万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2517465
• 关键词: T lymphocyte; athymic mouse; basement membrane; cadherins; cell adhesion; cell adhesion molecules; cell cell interaction; cell migration; extracellular matrix; human subject; immunologic memory; integrins; keratinocyte; laboratory mouse; mycosis fungoides lymphoma; skin; tissue /cell culture

The group of cutaneous T cell lymphomas (CTCL) typified by mycosis fungoides is characterized by the persistent infiltration of memory T lymphocytes into the epidermis. Alternatively, other cutaneous lymphomas (e.g., cutaneous B cell lymphoma or CBCL) are not characterized by epidermal migration. Rather, in CBCL the infiltrating cells are localized to the reticular (or deep dermis). These histological findings imply a specific recognition of the epidermis by T cells in mycosis fungoides. However, the precise mechanisms by which T cells penetrate the basement membrane and accumulate in the epidermis are unknown. The underlying hypothesis of the present proposal is that keratinocyte adhesion molecules are pivotal to epidermal migration of T cells in CTCL. This includes matrix molecules synthesized by keratinocytes (basement membrane) as well as their cell surface components (cell adhesion molecules or CAMs). Although the CD18/ICAM pathway has been postulated to play a major role in determining T cell adhesion to activated keratinocytes, ICAM is not expressed in basement membranes, and focal exocytosis of T cells has been observed in the absence of ICAM expression on nearby keratinocytes. These findings suggest that ICAM independent adhesion pathways exist in the skin that can be utilized by epidermotropic T cells. In this proposal we will identify ICAM independent pathways which operate in the adhesive recognition of keratinocytes by cutaneous T cells. As a model system we will use a cultured T cell line derived from patients with CTCL (HUT 78), freshly derived T cells from the skin and blood of patients with CTCL, and basal keratinocytes derived from neonatal foreskins (HFKs). This proposal has three objectives: 1) To determine how cutaneous T cells interact with the extracellular matrix deposited by cultured keratinocytes. These experiments will be focused on the function and regulation of the alpha3beta1 integrin receptor. 2) To determine how T cells interact with keratinocyte cell surface adhesion molecules other than ICAM. These experiments will be focused on the function and regulation of E-cadherin expressed by cutaneous T cells. 3) To determine how these adhesive events are coordinated in CTCL and contribute to epidermal homing in an in vivo model. These studies will provide valuable new information on the role of adhesion molecules in T cell epidermal trafficking in CTCL and cutaneous inflammation.

以真菌病为代表的皮肤T细胞淋巴瘤(CTCL)组 Fungoids的特点是记忆性T的持续渗透 淋巴细胞进入表皮。或者，其他皮肤淋巴瘤 (例如，皮肤B细胞淋巴瘤或CBCL)的特征不是 表皮迁移。相反，在CBCL中，浸润性细胞定位于 至网状(或深层真皮)。这些组织学发现暗示 真菌样肉芽肿中T细胞对表皮的特异性识别。 然而，T细胞穿透基底的确切机制 膜和堆积在表皮是未知的。潜在的 目前提出的假设是角质形成细胞黏附分子 对CTCL中T细胞的表皮迁移起关键作用。这包括 角质形成细胞(基底膜)合成的基质分子 作为它们的细胞表面成分(细胞黏附分子或CAM)。 尽管CD18/ICAM通路被认为在 确定T细胞与活化角质形成细胞的黏附，ICAM不是 在基底膜上表达，T细胞的局灶性胞吐 在邻近角质形成细胞上没有ICAM表达的情况下观察。这些 研究结果表明，皮肤中存在ICAM非依赖的黏附途径 它可以被亲表T细胞利用。在本提案中，我们将 确定在粘合剂中工作的ICAM独立路径 皮肤T细胞对角质形成细胞的识别作用作为一个模型系统，我们 将使用来自CTCL患者的培养T细胞系(HUT 78)， 从CTCL患者的皮肤和血液中新鲜提取的T细胞，以及 新生儿包皮来源的基底层角质形成细胞(HFK)。这项建议 有三个目标：1)确定皮肤T细胞如何与 培养的角质形成细胞沉积的细胞外基质。这些 实验将集中在功能和调节的基础上。 α3β1整合素受体。2)确定T细胞如何与 角质形成细胞表面ICAM以外的黏附分子。这些 实验将集中在E-钙粘附素的功能和调节上 由皮肤T细胞表达。3)确定这些粘合事件如何 是在CTCL中协调的，并有助于体内的表皮归巢 模特。这些研究将提供有价值的新信息，以了解 CTCL和皮肤T细胞表皮转运中的黏附分子 发炎。