Stein J V, Rot A, Luo Y, Narasimhaswamy M, Nakano H, Gunn M D, Matsuzawa A, Quackenbush E J, Dorf M E, von Andrian U H
The Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Exp Med. 2000 Jan 3;191(1):61-76. doi: 10.1084/jem.191.1.61.
T cell homing to peripheral lymph nodes (PLNs) is defined by a multistep sequence of interactions between lymphocytes and endothelial cells in high endothelial venules (HEVs). After initial tethering and rolling via L-selectin, firm adhesion of T cells requires rapid upregulation of lymphocyte function-associated antigen 1 (LFA-1) adhesiveness by a previously unknown pathway that activates a Galpha(i)-linked receptor. Here, we used intravital microscopy of murine PLNs to study the role of thymus-derived chemotactic agent (TCA)-4 (secondary lymphoid tissue chemokine, 6Ckine, Exodus-2) in homing of adoptively transferred T cells from T-GFP mice, a transgenic strain that expresses green fluorescent protein (GFP) selectively in naive T lymphocytes (T(GFP) cells). TCA-4 was constitutively presented on the luminal surface of HEVs, where it was required for LFA-1 activation on rolling T(GFP) cells. Desensitization of the TCA-4 receptor, CC chemokine receptor 7 (CCR7), blocked T(GFP) cell adherence in wild-type HEVs, whereas desensitization to stromal cell-derived factor (SDF)-1alpha (the ligand for CXC chemokine receptor 4 [CXCR4]) did not affect T(GFP) cell behavior. TCA-4 protein was not detected on the luminal surface of PLN HEVs in plt/plt mice, which have a congenital defect in T cell homing to PLNs. Accordingly, T(GFP) cells rolled but did not arrest in plt/plt HEVs. When TCA-4 was injected intracutaneously into plt/plt mice, the chemokine entered afferent lymph vessels and accumulated in draining PLNs. 2 h after intracutaneous injection, luminal presentation of TCA-4 was detectable in a subset of HEVs, and LFA-1-mediated T(GFP) cell adhesion was restored in these vessels. We conclude that TCA-4 is both required and sufficient for LFA-1 activation on rolling T cells in PLN HEVs. This study also highlights a hitherto undocumented role for chemokines contained in afferent lymph, which may modulate leukocyte recruitment in draining PLNs.
T细胞归巢至外周淋巴结（PLN）是由淋巴细胞与高内皮微静脉（HEV）中的内皮细胞之间多步骤的相互作用所定义的。在通过L-选择素进行初始的拴系和滚动之后，T细胞的牢固黏附需要通过一条激活与Gα(i)相连受体的未知途径，快速上调淋巴细胞功能相关抗原1（LFA-1）的黏附性。在此，我们利用小鼠PLN的活体显微镜技术，研究胸腺来源趋化因子（TCA）-4（二级淋巴组织趋化因子、6Ckine、Exodus-2）在来自T-GFP小鼠（一种在幼稚T淋巴细胞（T(GFP)细胞）中选择性表达绿色荧光蛋白（GFP）的转基因品系）的过继转移T细胞归巢中的作用。TCA-4组成性地呈递于HEV的管腔表面，在滚动的T(GFP)细胞上LFA-1激活需要该表面。TCA-4受体CC趋化因子受体7（CCR7）脱敏可阻断野生型HEV中T(GFP)细胞的黏附，而对基质细胞衍生因子（SDF）-1α（CXC趋化因子受体4 [CXCR4]的配体）脱敏并不影响T(GFP)细胞行为。在plt/plt小鼠的PLN HEV管腔表面未检测到TCA-4蛋白，该小鼠在T细胞归巢至PLN方面存在先天性缺陷。相应地，T(GFP)细胞在plt/plt HEV中滚动但未停滞。当将TCA-4皮内注射到plt/plt小鼠体内时，趋化因子进入输入淋巴管并在引流的PLN中积聚。皮内注射2小时后，在一部分HEV中可检测到TCA-4的管腔呈递，并且在这些血管中恢复了LFA-1介导的T(GFP)细胞黏附。我们得出结论，TCA-4对于PLN HEV中滚动T细胞上的LFA-1激活既是必需的也是充分的。这项研究还突出了输入淋巴中趋化因子迄今未被记录的作用，其可能调节引流PLN中的白细胞募集。
