Wingren Anette Gjorloff, Parra Eduardo, Varga Mikael, Kalland Terje, Sjogren Hans-Olov, Hedlund Gunnar, Dohlsten Mikael
The Wallenberg Laboratory, Department of Tumor Immunology, University of Lund, Box 7031, S-220 07, Lund, Sweden.
Pharmacia Immunology Oncology, Scheelevägen 22, S-223 63, Lund, Sweden.
Crit Rev Immunol. 2017;37(2-6):463-481. doi: 10.1615/CritRevImmunol.v37.i2-6.130.
Two signals are required for induction of cell proliferation and cytokine production in resting T cells. Occupancy of the T cell receptor by antigen/MHC complexes delivers the first signal to the T cell, while the second signal is provided by interaction with costimulatory ligands on APC. CD2, LFA-1, and CD28 are the major costimulatory and adhesive molecules on T cells and bind to the LFA-3, ICAM-1 and B7 ligands, respectively, on APC. LFA-3 plays a central role for naive and memory T helper cells during the early phase of an immune response. The LFA-3/CD2 pathway initiates strong antigen-independent cell adhesion, substantial expansion of naive T helper cells, and induction of large amounts of IFN-γ in memory cells. The release of IFN-γ may upregulate expression of ICAM-1 and B7 on APC and allows multiple adhesion pathways to amplify the immune response. The LFA- 1/ICAM-l pathway stimulates adhesion and cell proliferation more efficiently in memory T helper cells than in naive cells. Further, the results suggest that naive T helper cells express functionally inactive LFA-1 molecules on the cell surface, which may have a physiological role in keeping these cells in a resting state. B7 costimulation superinduces IL-2 production in both naive and memory T helper cells and generates long-lasting cell proliferation. This permits transition from an autocrine to a paracrine immune response. Coexpression of B7/LFA-3 provides an optimal APC function and enables a vigorous T cell response to minute amounts of antigen. AP-1 and NF-κB transcription factors are involved in the induction of several cytokine gene promoters and play a central role in the regulation of IL-2 gene transcription. LFA-3 costimulation only moderately enhances AP-1 DNA-binding activity and does not influence the NF-κB activity induced by TCR engagement, whereas B7 costimulation induces large amounts of NF-κB and AP-1 activity in T helper cells. The costimulatory ligands represent a family of adhesion molecules with considerable redundancy. Interfamily redundancy of LFA-3, B7, and ICAM ligands offers an opportunity to regulate distinct T cell response profiles in various microenvironments at separate time points of an immune response.
静息T细胞诱导细胞增殖和细胞因子产生需要两种信号。抗原/MHC复合物占据T细胞受体为T细胞传递第一个信号，而第二个信号则由与抗原呈递细胞（APC）上共刺激配体的相互作用提供。CD2、淋巴细胞功能相关抗原-1（LFA-1）和CD28是T细胞上主要的共刺激和黏附分子，分别与APC上的淋巴细胞功能相关抗原-3（LFA-3）、细胞间黏附分子-1（ICAM-1）和B7配体结合。在免疫反应早期，LFA-3对初始和记忆性T辅助细胞起着核心作用。LFA-3/CD2途径启动强烈的抗原非依赖性细胞黏附、初始T辅助细胞的大量扩增以及记忆细胞中大量γ干扰素（IFN-γ）的诱导。IFN-γ的释放可能上调APC上ICAM-1和B7的表达，并使多种黏附途径放大免疫反应。LFA-1/ICAM-1途径在记忆T辅助细胞中比在初始细胞中更有效地刺激黏附和细胞增殖。此外，结果表明初始T辅助细胞在细胞表面表达功能无活性的LFA-1分子，这可能在使这些细胞保持静息状态方面具有生理作用。B7共刺激在初始和记忆T辅助细胞中都超诱导白细胞介素-2（IL-2）的产生，并产生持久的细胞增殖。这允许从自分泌免疫反应转变为旁分泌免疫反应。B7/LFA-3的共表达提供了最佳的APC功能，并使T细胞对微量抗原产生强烈反应。激活蛋白-1（AP-1）和核因子κB（NF-κB）转录因子参与多种细胞因子基因启动子的诱导，并在IL-2基因转录的调节中起核心作用。LFA-3共刺激仅适度增强AP-1的DNA结合活性，且不影响T细胞受体（TCR）结合诱导的NF-κB活性，而B7共刺激在T辅助细胞中诱导大量的NF-κB和AP-1活性。共刺激配体代表了一个具有相当冗余性的黏附分子家族。LFA-3、B7和ICAM配体的家族间冗余为在免疫反应的不同时间点调节不同微环境中不同的T细胞反应谱提供了机会。
