FUNCTIONAL CONSEQUENCES OF COSTIMULATION THROUGH LFA-1

LFA-1是公认的粘附分子，在T细胞活化和归巢中起重要作用。此外，LFA-1涉及提供共刺激信号，其可以与通过TcR复合物转导的信号协同工作以启动T细胞活化。我们最近发现，当共刺激仅限于LFA-1/ICAM-1相互作用时，抗原呈递有效地驱动CD 4 + T细胞进入细胞周期，但这些细胞最终死于凋亡。通过补充正常水平的外源性IL-2或通过用B7-1+抗原呈递细胞呈递的抗原再刺激可以恢复T细胞存活。在这两种情况下，当这些T细胞在LFA-1共刺激的情况下已经用抗原引发时，测试它们产生细胞因子的能力，它们分泌正常水平的IL-2和IFN-γ，但不分泌可检测水平的IL-2。这些数据表明，如果初始T细胞首先遇到表达ICAM-1而不是B7的APC上的抗原，（例如，诱导表达II类和ICAM-1的非造血细胞），他们将倾向于Th 1型的建议是评估细胞和分子事件，这些事件决定了在LFA-1共刺激的情况下用抗原引发的T细胞的细胞因子潜力。刺激，并评估这些T细胞在体内的免疫调节潜力。我们将通过三个具体目标来实现这一目标。具体目标1：确定在LFA-1/ICAM-1相互作用的存在下，不同的共刺激分子如何调节由抗原引发的CD 4 + T细胞的存活和分化。具体目标二：分析在LFA-1介导的共刺激背景下引发T细胞后导致IL-4表达失败的分子事件。具体目标3：使用新鲜分离的APC和体内T细胞应答评估LFA-1共刺激在Th 1亚群偏斜中的作用。

LFA-1 is a well recognized adhesion molecule, that plays an important role in T cell activation and homing. In addition, LFA-1 has been implicated in providing co-stimulatory signals that can work in concert with signals transduced through the TcR complex to initiate T cell activation. We have recently found that, when co-stimulation is limited to LFA-1/ICAM-1 interactions, antigen presentation efficiently drives CD4+ T cells into the cell cycle, but these cells ultimately die of apoptosis. T cell survival can be restored by supplementation with normal levels of exogenous IL-2 or by restimulation with antigen presented by B7-1+ antigen presenting cells. In both cases, when these T cells have been primed with antigen in the context of LFA-1 co-stimulation are tested for their ability to produce cytokines, they secrete normal levels of IL-2 and IFN-gamma, but do not secrete detectable levels of IL-2. These data suggest that if naive T cells first encounter antigen on APC that express ICAM-1, but not B7 (for example, non-hematopoietic cells induced to express class II and ICAM-1), they will be skewed toward Th1-type proposal are to assess the cellular and molecular events that determine the cytokine potential of T cells that are primed with antigen in the context of LFA-1 co-stimulation and to evaluate the immunoregulatory potential of these T cells in vivo. We will do this through three specific aims. Specific Aim 1: Determine how different co-stimulatory molecules regulate the survival and differentiation of CD4+ T cells primed by antigen in the presence of LFA-1/ICAM-1 interactions. Specific Aim 2: Analyze the molecular events that account for the failure to express IL-4 after T cells have been primed in the context of LFA-1-mediated co-stimulation. Specific Aim 3: Assess the role of LFA-1 co-stimulation in Th1 subset skewing using freshly isolated APC and in vivo T cell responses.