MURINE T LYMPHOCYTE SUBSETS AND ALLOGRAFT REJECTION

T细胞、B细胞和抗原呈递细胞之间的相互作用启动 由细胞因子和细胞因子介导和调节的免疫应答 表面相互作用CD 4 + T细胞的亚群已经在 分泌性淋巴因子的基础。CD 8 + T细胞的亚群尚未被发现。 详细描述。提出的研究总体目标 项目2是确定管理国家机构职能的机制的特点， T淋巴细胞负责同种异体移植物的排斥反应， 重点是CD 8 + T细胞。我们将定义CD 8 + T细胞亚群 与单个主要组织相容性复合体（MHC）抗原反应， 以及确定控制这些T细胞反应的机制， 细胞亚群我们将主要研究对I类MHC抗原的反应， 尤其是H-2Ld。为实现这一目标，提出了三个具体目标 总体目标：1）确定细胞因子和细胞表面分子 参与激活幼稚和致敏的CD 8 + T细胞反应， 用H-2Ld I类MHC抗原，使用来自转基因小鼠的T细胞， CD 8 + T细胞表达抗原特异性的转基因（Tg）α/β T 细胞受体（TCR），其与H-2Ld同种异体抗原反应。初始cd 8 + T 细胞将从未致敏的脾脏和淋巴结中获得。敏化 CD 8 + T细胞将从引流淋巴结的部位获得。 腹腔内移植后排斥同种异体皮肤或脾脏 注射同种异体细胞。特定淋巴因子的作用（包括 IL-1、IL-2、IL-4、IL-10和IL-12）和细胞表面分子（包括 B7-1、B7-2、CD 28、CTLA-4、LFA-1、ICAM-1）活化增殖， 淋巴因子的产生和细胞溶解活性的获得将是 使用中和单克隆抗体（mAb）和各种 抗原呈递细胞（APC）群体; 2）衍生克隆 代表各种CD 8 + T细胞亚群，并比较 这些克隆与那些控制幼稚的克隆一起调节各种功能， CD 8 + T细胞。为实现具体目标1而提出的实验应 确定必要条件（淋巴因子和细胞表面分子） 刺激CD 8 + Tg T细胞产生那些淋巴因子， CD 4 + T辅助细胞（Th）的不同亚群，即白细胞介素（IL） IL-2和干扰素-γ（IFN-γ）对Th 1和IL-4、IL-5、IL-6和IL-10的影响 对于Th 2。利用这些信息，我们将定义导致 选择性地激活一个或另一个子集，我们将得出 分泌不同淋巴因子阵列的CD 8 + Tg T细胞的克隆。我们 将确定代表CD 8+亚群的克隆的功能，测量 产生淋巴因子、提供B细胞帮助和细胞溶解活性 由穿孔素和Fas介导。我们还将评估各种能力， 调节初始CD 4+和CD 8 + T细胞以及CD 4 + T细胞的应答的CD 8+亚群 和CD 8+克隆;以及3）基于通过以下获得的信息： 其他具体目标，开发抑制同种异体移植物的策略 排斥反应可能的疗法包括使用与以下物质反应的mAb： 特定的细胞因子和/或mAb或其它与细胞反应的试剂 特定T细胞亚群或APC上的表面结构。

Interactions among T cells, B cells, and antigen-presenting cells initiate immune responses which are mediated and regulated by cytokines and by cell surface interactions. Subsets of CD4+ T cells have been identified on the basis of secreted lymphokines. Subsets of CD8+ T cells have not been characterized in detail. The general goal of the research proposed in Project 2 is to characterize the mechanisms that regulate the functions of T lymphocytes which are responsible for rejection of allografts, with emphasis placed on CD8+ T cells. We will define CD8+ T cell subsets reacting to individual major histocompatibility complex (MHC) antigens as well as determining the mechanisms that control the responses of these T cell subsets. We will study mainly the response to class I MHC antigens, particularly H-2Ld. Three Specific Aims are proposed to accomplish this general goal: 1) To determine the cytokines and cell surface molecules that are involved in activating naive and primed CD8+ T cells reactive with H-2Ld class l MHC antigen, using T cells from transgenic mice whose CD8+ T cells express an antigen-specific, transgenic (Tg), alpha/beta T cell receptor (TCR) which reacts with H-2Ld alloantigen. Naive CD8+ T cells will be obtained from unprimed spleen and lymph nodes. Sensitized CD8+ T cells will be obtained from lymph nodes draining the site of a rejecting skin allograft or from the spleen following intraperitoneal injection of allogeneic cells. The role of specific lymphokines (including IL-1, IL-2, lL-4, lL-1O and lL-12) and cell surface molecules (including B7-1, B7-2, CD28, CTLA-4, LFA-1, ICAM-1) in activation for proliferation, lymphokine production, and acquisition of cytolytic activity will be determined, using neutralizing monoclonal antibodies (mAb) and various populations of antigen-presenting cells (APC); 2) To derive clones representing various CD8+ T cell subsets and compare the mechanisms that regulate various functions of these clones with those controlling naive CD8+ T cells. The experiments proposed to accomplish Specific Aim 1 should define the essential conditions (lymphokines and cell surface molecules) for stimulating CD8+ Tg T cells to produce those lymphokines that have distinguished subsets of CD4+ T helper (Th) cells, namely interleukin (IL) 2 and interferon-gamma (IFN-gamma) for Th1 and IL-4, lL-5, lL-6, and lL-10 for Th2. Using this information, we will define conditions that lead selectively to activation of one or another subset, and we will derive clones of CD8+ Tg T cells that secrete different lymphokines arrays. We will determine functions of clones representing CD8+ subsets, measuring lymphokine production, provision of B cell help, and cytolytic activity mediated by perforin and Fas. We also will evaluate the ability of various CD8+ subsets to regulate responses of naive CD4+ and CD8+ T cells and CD4+ and CD8+ clones in vitro; and 3) Based on the information obtained through the other Specific Aims, to develop strategies for suppressing allograft rejection. Possible therapies include the use of mAb reactive with particular cytokines and/or mAb or other reagents that react with cell surface structures on the particular T cell subsets or APC.