Mongini P K, Blessinger C A, Dalton J P
Institute of Molecular Immunology, Hospital for Joint Diseases, New York, NY 10003.
J Immunol. 1991 Mar 15;146(6):1791-800.
The affinity of Ag interaction with a B cell's membrane IgM (mIgM) receptors has long been considered to play a critical role in the in vivo clonal selection of B lymphocytes. This study has examined a possible basis for this affinity selection at the level of Ag induction of sequential B cell activation phenomena, i.e., elevated membrane class II MHC expression (G0* excitation), G1 entry, and S phase entry. Functional experiments with model bivalent Ag, i.e., a group of murine mAb of diverse intrinsic binding affinities for human IgM, revealed that the minimal affinity requisites for inducing the above phenomena vary significantly. At a ligand concentration of 100 micrograms/ml, the induction of increased class II MHC expression, G1 entry, and S phase had minimal affinity thresholds of Ka approximately 0.2 to 2 x 10(6) M-1; approximately 7 x 10(6) M-1; and approximately 1 x 10(8) M-1, respectively. Pulsing studies revealed that whereas high affinity ligand was essential at later periods in the prolonged (greater than 24 h) signaling period that leads to S phase entry, mAb with significantly lower affinity were competent at signaling during the first 24 h. Because all but the lowest affinity ligand (Ka = 2 x 10(5) M-1) could effectively modulate mIgM, and furthermore, because B cells show a substantial increase in surface area during activation, it appears likely that one factor contributing to the higher affinity requirements for induction of late activation phenomena is a progressive decrease in the density of mIgM on the responsive B cells. These studies suggest that whereas only a small proportion of B cells, i.e., those with relatively high affinity for an antigenic epitope, will be triggered to clonally expand on encountering a paucivalent Ag in the absence of T cell help, a much wider spectrum of the B cell repertoire will be triggered to a state of partial activation. How the presence of ancillary T cells and cytokines may facilitate the full clonal expansion of these latter cells is discussed.
长期以来，人们一直认为抗原与B细胞膜免疫球蛋白M（mIgM）受体相互作用的亲和力在B淋巴细胞的体内克隆选择中起着关键作用。本研究在抗原诱导连续B细胞激活现象的层面上，研究了这种亲和力选择的可能基础，即膜II类主要组织相容性复合体表达升高（G0*激发）、进入G1期和进入S期。使用模型二价抗原进行的功能实验，即一组对人IgM具有不同内在结合亲和力的鼠单克隆抗体，结果显示诱导上述现象所需的最小亲和力要求差异显著。在配体浓度为100微克/毫升时，诱导II类主要组织相容性复合体表达增加、进入G1期和进入S期的最小亲和力阈值分别约为Ka = 0.2至2×10⁶ M⁻¹；约7×10⁶ M⁻¹；和约1×10⁸ M⁻¹。脉冲研究表明，虽然高亲和力配体在导致进入S期的延长（大于24小时）信号传导期的后期至关重要，但亲和力明显较低的单克隆抗体在前24小时的信号传导中也有作用。因为除了最低亲和力配体（Ka = 2×10⁵ M⁻¹）外，所有配体都能有效调节mIgM，而且，由于B细胞在激活过程中表面积会大幅增加，所以导致后期激活现象诱导所需更高亲和力要求的一个因素可能是反应性B细胞上mIgM密度的逐渐降低。这些研究表明，在没有T细胞帮助的情况下，遇到多价抗原时，只有一小部分B细胞，即那些对抗原表位具有相对高亲和力的B细胞，会被触发进行克隆扩增，而更广泛的B细胞库将被触发进入部分激活状态。本文还讨论了辅助性T细胞和细胞因子的存在如何促进这些后期细胞的完全克隆扩增。
