MECHANISMS OF T LYMPHOCYTE MIGRATION INTO SKIN

T 淋巴细胞迁移至皮肤的机制

• 批准号: 2081077
• 负责人: ELIZABETH A WAYNER
• 金额: $ 15.32万
• 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 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2081077
• 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.

皮肤T细胞淋巴瘤（CTCL）以真菌病为典型 蕈样肉芽肿的特征是记忆T细胞的持续浸润 淋巴细胞进入表皮。 或者，其他皮肤淋巴瘤 (e.g.,皮肤B细胞淋巴瘤或CBCL）的特征不在于 表皮迁移 相反，在CBCL中，浸润细胞是局部的， 至网状组织（或深层真皮）。 这些组织学结果表明， 蕈样肉芽肿中T细胞对表皮的特异性识别。 然而，T细胞穿透基底的精确机制 膜和积累在表皮是未知的。 底层 本发明的假设是角质形成细胞粘附分子 是CTCL中T细胞表皮迁移的关键。 这包括 由角质形成细胞（基底膜）合成的基质分子 作为它们的细胞表面组分（细胞粘附分子或CAM）。 尽管CD 18/ICAM途径被认为在肿瘤的发生发展中起主要作用， 确定T细胞粘附到活化的角质形成细胞，ICAM不是 在基底膜中表达，T细胞的局灶性胞吐作用已经被证实。 在附近的角质形成细胞上没有ICAM表达的情况下观察到。 这些 结果表明，皮肤中存在ICAM独立的粘附途径 可以被亲表皮T细胞利用。 在本提案中，我们将 确定在粘合剂中起作用的ICAM独立途径 皮肤T细胞对角质形成细胞的识别。 作为模型系统， 将使用来自CTCL患者的培养T细胞系（HUT 78）， 来自CTCL患者的皮肤和血液的新鲜衍生的T细胞，和 来源于新生儿包皮的基底角质形成细胞（HFKs）。 这项建议 有三个目标：1）确定皮肤T细胞如何与 由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 α 3 β 1整合素受体。2)为了确定T细胞如何与 角质形成细胞表面粘附分子，而不是ICAM。 这些 本实验将重点研究E-cadherin的功能和调控 由皮肤T细胞表达。3)为了确定这些粘连事件 在CTCL中协调，并有助于体内表皮归巢 模型 这些研究将提供关于以下方面作用的宝贵新资料： CTCL和皮肤中T细胞表皮运输中的粘附分子 炎症