Ranheim E A, Kipps T J
Department of Medicine, University of California, San Diego, La Jolla 92093-0663.
J Exp Med. 1993 Apr 1;177(4):925-35. doi: 10.1084/jem.177.4.925.
Cognate interactions between antigen-presenting B and T cells play crucial roles in immunologic responses. T cells that have been activated via the crosslinking of CD3 are able to induce B cell proliferation and immunoglobulin secretion in a major histocompatibility complex-unrestricted and contact-dependent manner. We find that such activated human CD4+ T cells, but not control Ig-treated T cells, may induce normal or leukemic B cells to express B7/BB1 and significantly higher levels of CD54 intercellular adhesion molecule 1 via a process that also requires direct cell-cell contact. To discern what cell surface molecule(s) may be responsible for signalling B cells to express B7/BB1, we added various monoclonal antibodies (mAbs) specific for T or B cell accessory molecules or control mAbs to cocultures of alpha-CD3-activated T cells and resting B cells. We find that only alpha-CD40 mAbs can significantly inhibit the increased expression of B7/BB1, suggesting that the ligand for CD40 expressed on activated T cells may be an important inducer of B7/BB1 expression. Subsequent experiments in fact demonstrate that alpha-CD40 mAbs, but not control mAbs, induce changes in B cell phenotype similar to those induced by activated T cells when the mAbs are presented on Fc gamma RII (CDw32)-expressing L cells. These phenotypic changes have significant effects on B cell function. Whereas chronic lymphocytic leukemia (CLL) B cells normally are very poor stimulators in allogeneic mixed lymphocyte reactions (MLRs), CLL-B cells preactivated via CD40 crosslinking are significantly better presenters of alloantigen, affecting up to 30-fold-greater stimulation of T cell proliferation than that induced by control treated or nontreated CLL-B cells. Similarly, the MLR of T cells stimulated by allogeneic nonleukemic B cells can be enhanced significantly if the stimulator B cells are preactivated via CD40 crosslinking. The enhanced MLR generated by such preactivated B cells may be inhibited by blocking B7/BB1-CD28 interaction with CTLA4Ig. These studies demonstrate a novel, CD40-dependent pathway for inducing B cell expression of B7/BB1 and enhancing B cell antigen-presenting cell activity that can be initiated via cell-cell contact with alpha-CD3-stimulated CD4+ T cells.
抗原呈递B细胞与T细胞之间的同源相互作用在免疫反应中起着关键作用。通过CD3交联激活的T细胞能够以主要组织相容性复合体非限制性和接触依赖性方式诱导B细胞增殖和免疫球蛋白分泌。我们发现，这种活化的人CD4+T细胞，而非对照Ig处理的T细胞，可能通过一个同样需要直接细胞-细胞接触的过程，诱导正常或白血病B细胞表达B7/BB1以及显著更高水平的细胞间黏附分子1（CD54）。为了辨别哪些细胞表面分子可能负责向B细胞发出信号以表达B7/BB1，我们将各种针对T或B细胞辅助分子的单克隆抗体（mAb）或对照mAb添加到α-CD3激活的T细胞与静息B细胞的共培养物中。我们发现只有α-CD40 mAb能够显著抑制B7/BB1表达的增加，这表明活化T细胞上表达的CD40配体可能是B7/BB1表达的重要诱导物。后续实验事实上证明，当mAb呈现在表达FcγRII（CDw32）的L细胞上时，α-CD40 mAb而非对照mAb能诱导B细胞表型发生类似于活化T细胞诱导的变化。这些表型变化对B细胞功能有显著影响。慢性淋巴细胞白血病（CLL）B细胞在同种异体混合淋巴细胞反应（MLR）中通常是非常差的刺激细胞，而通过CD40交联预激活的CLL-B细胞是更好的同种异体抗原呈递细胞，与对照处理或未处理的CLL-B细胞相比，其对T细胞增殖的刺激作用高达30倍。同样，如果刺激B细胞通过CD40交联预激活，同种异体非白血病B细胞刺激的T细胞的MLR可显著增强。这种预激活B细胞产生的增强MLR可通过用CTLA4Ig阻断B7/BB1-CD28相互作用而受到抑制。这些研究证明了一条新的、依赖CD40的途径，用于诱导B细胞表达B7/BB1并增强B细胞抗原呈递细胞活性，该途径可通过与α-CD3刺激的CD4+T细胞进行细胞-细胞接触而启动。
