Fibronectin promotes proliferation of naive and memory T cells by signaling through both the VLA-4 and VLA-5 integrin molecules.
Fibronectin promotes proliferation of naive and memory T cells by signaling through both the VLA-4 and VLA-5 integrin molecules.
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纤连蛋白通过 VLA-4 和 VLA-5 整合素分子发出信号，促进初始 T 细胞和记忆 T 细胞的增殖。
DOI：
10.4049/jimmunol.145.3.785
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发表时间：
1990
影响因子：
4.4
通讯作者：
P. E. Lipsky
中科院分区：
文献类型：
--
作者：
Laurie S. Davis;N. Oppenheimer;J. L. Bednarczyk;Bradley W. McIntyre;P. E. Lipsky
纯化纤维连接蛋白共刺激人T细胞DNA合成的能力进行了检测。低浓度的固定纤维连接蛋白，而不是可溶性纤维连接蛋白，增强了抗cd3诱导的高度纯化的人T细胞的增殖。在没有抗cd3刺激的情况下，固定纤维连接蛋白单独或在IL-2或二丁酸佛酚存在时都不能诱导T细胞增殖。虽然纤维连接蛋白在血清中存在高浓度，但当细胞在含血清的培养基中培养时，固定的纤维连接蛋白能够共同刺激T细胞增殖。固定化I型胶原不增强抗cd3刺激的T细胞反应，而明胶（变性胶原）和层粘连蛋白能够适度增强抗cd3刺激的T细胞反应。然而，明胶的作用似乎是间接的，因为它不能在缺乏纤维连接蛋白的培养基中增强反应。固定纤维连接蛋白增强了CD4+和CD8+ T细胞亚群中CD45RA暗淡和CD45RA明亮亚群的抗cd3诱导增殖，尽管具有CD45RA暗淡表型的细胞被较低浓度的固定纤维连接蛋白共同刺激。固定纤维连接蛋白对抗cd3诱导的增殖的增强作用被CD29整合素- 1链（4B4）的单抗完全抑制，而不被其他多种单抗抑制。与其对增殖的影响相反，4B4仅部分阻断T细胞与抗cd3和纤维连接蛋白包被的大孔细胞的结合。这些发现表明，纤维连接蛋白与其受体之间的相互作用将信号转导到T细胞，而不仅仅是稳定抗CD3和CD3复合物之间的相互作用。进一步的实验证实了这一观察结果。因此，当纤维连接蛋白固定在一个单独的表面时，它可以增强抗cd3反应。固定化纤维连接蛋白诱导的抗cd3刺激增殖的增强也被针对vla4或vla5的单抗部分抑制，并被两种单抗的联合完全抑制。对vla4的单抗不仅阻断了固定纤维连接蛋白增强抗cd3诱导的T细胞增殖的能力，而且直接共刺激T细胞反应。因此，至少有两种纤维连接蛋白受体参与了纤维连接蛋白介导的T细胞增殖的共刺激。这些研究表明，信号通过纤维连接蛋白受体vla4和vla5转导，增强T细胞反应，因此暗示细胞外基质蛋白纤维连接蛋白在体内调节T细胞反应性方面具有重要影响。
The capacity of purified fibronectin to costimulate human T cell DNA synthesis was examined. Low concentrations of immobilized fibronectin, but not soluble fibronectin, augmented anti-CD3-induced proliferation of highly purified human T cells. In the absence of anti-CD3 stimulation, immobilized fibronectin did not induce T cell proliferation alone or in the presence of IL-2 or phorbol dibutyrate. Although fibronectin is present in high concentrations in the serum, immobilized fibronectin was able to costimulate T cell proliferation when cells were cultured in serum-containing medium. Immobilized collagen type I did not enhance anti-CD3 stimulated T cell responses, whereas gelatin (denatured collagen) and laminin were able to enhance anti-CD3 stimulated T cell responses modestly. The effects of gelatin, however, appeared to be indirect, because it could not enhance responses in medium devoid of fibronectin. Immobilized fibronectin enhanced anti-CD3 induced proliferation of both CD45RA dim and CD45RA bright subsets within both the CD4+ and CD8+ subpopulations of T cells, although cells with the CD45RA dim phenotype were costimulated by lower concentrations of immobilized fibronectin. Enhancement of anti-CD3 induced proliferation by immobilized fibronectin was completely inhibited by a mAb to CD29, the integrin beta 1-chain (4B4) and not by a variety of other mAb. In contrast to its effects on proliferation, 4B4 only partially blocked T cell binding to anti-CD3 and fibronectin-coated macrowells. These findings suggested that the interaction between fibronectin and its receptor transduced a signal to the T cell and did not merely stabilize the interaction between anti-CD3 and the CD3 complex. Further experiments confirmed this observation. Thus fibronectin could enhance anti-CD3 responses when it was immobilized to a separate surface. The augmentation of anti-CD3 stimulated proliferation induced by immobilized fibronectin was also inhibited partially by mAb to either VLA-4 or VLA-5 and completely by a combination of the two mAb. The mAb to VLA-4 not only blocked the capacity of immobilized fibronectin to enhance anti-CD3-induced T cell proliferation but also directly costimulated T cell responses. Thus, at least two fibronectin receptors are involved in fibronectin-mediated costimulation of T cell proliferation. These studies indicate that signals are transduced through the fibronectin receptors, VLA-4 and VLA-5, that augment T cell responses and therefore implicate the extracellular matrix protein fibronectin as an important influence regulating T cell responsiveness in vivo.