Picker L J, Treer J R, Ferguson-Darnell B, Collins P A, Buck D, Terstappen L W
Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75235-9072.
J Immunol. 1993 Feb 1;150(3):1105-21.
Conventional virgin lymphocytes of a given class show relatively homogeneous recirculation through secondary lymphoid tissues, whereas memory/effector populations are composed of distinct subsets with differential, often tissue-selective migratory capability. In keeping with these observations, CD45RAhigh/ROlow "virgin" T cells in human peripheral blood uniformly express the peripheral lymph node homing receptor (HR) L-selectin, whereas among the CD45RAlow/ROhigh "memory/effector" subset, the expression of this HR is bimodal. To investigate the mechanisms responsible for the generation of memory/effector T cell subsets with differential homing potential, we developed a multiparameter flow cytometric technique that defines a common pathway of post-thymic T cell differentiation in secondary lymphoid tissues. Our analyses indicate that the virgin to memory T cell transition is characterized by a stepwise, unidirectional progression through distinct CD45RA+/RO+ intermediates that allow the in vivo discrimination of early, middle, and late transitional T cells. In normal peripheral blood, few T cells with a transitional phenotype are identified, but in secondary lymphoid tissues, 2 to 10% of T cells have this phenotype, including those CD45RA+ T cells that 1) are morphologically blasts, 2) are in S or G2/M phase of the cell cycle, or 3) express activation Ag. General adhesion molecules (LFA-1, LFA-3, ICAM-1) are uniformly up-regulated concordant with changes in T cell expression of CD45RA/RO in all tissues examined. Early in the transition, L-selectin is also uniformly up-regulated, but in subsequent stages, T cell expression of this HR is preferentially down-regulated in mucosal lymphoid tissues, and retained in peripheral lymph node. Differential regulation of L-selectin can also be demonstrated in vitro by the activation of virgin T cells in the presence of specific cytokines--IL-2 induces L-selectin down-regulation, whereas IL-6 and particularly TGF-beta 1 promote L-selectin up-regulation. Taken together, these findings support the hypothesis that local microenvironments within particular secondary lymphoid tissues influence HR expression at the time of CD45RA/RO conversion, and thereby contribute to the formation of CD45RAlow/ROhigh memory/effector T cell populations with tissue-selective homing behavior.
某一特定类型的传统未接触过抗原的淋巴细胞通过次级淋巴组织循环时表现出相对均一性，而记忆/效应细胞群体则由具有不同的、通常是组织选择性迁移能力的不同亚群组成。与这些观察结果一致，人类外周血中CD45RA高/RO低的“未接触过抗原的”T细胞均一性地表达外周淋巴结归巢受体（HR）L-选择素，而在CD45RA低/RO高的“记忆/效应”亚群中，这种HR的表达呈双峰模式。为了研究导致具有不同归巢潜能的记忆/效应T细胞亚群产生的机制，我们开发了一种多参数流式细胞术技术，该技术定义了次级淋巴组织中胸腺后T细胞分化的共同途径。我们的分析表明，从未接触过抗原的T细胞向记忆T细胞的转变的特征是通过不同的CD45RA+/RO+中间阶段进行逐步、单向的进展，这使得能够在体内区分早期、中期和晚期过渡性T细胞。在正常外周血中，很少能鉴定出具有过渡表型的T细胞，但在次级淋巴组织中，2%至10%的T细胞具有这种表型，包括那些1）形态上为母细胞、2）处于细胞周期的S期或G2/M期、或3）表达活化抗原的CD45RA+ T细胞。在所有检测的组织中，一般黏附分子（LFA-1、LFA-3、ICAM-1）与T细胞CD45RA/RO表达的变化一致地均一性上调。在转变早期，L-选择素也均一性上调，但在随后阶段，该HR在黏膜淋巴组织中的T细胞表达优先下调，而在外周淋巴结中得以保留。L-选择素的差异调节在体外也可通过在特定细胞因子存在下激活未接触过抗原的T细胞来证明——IL-2诱导L-选择素下调，而IL-6尤其是TGF-β1促进L-选择素上调。综上所述，这些发现支持这样一种假说，即特定次级淋巴组织内的局部微环境在CD45RA/RO转换时影响HR表达，从而有助于形成具有组织选择性归巢行为的CD45RA低/RO高记忆/效应T细胞群体。
