Blair David A, Lefrançois Leo
Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1319, USA.
Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15045-50. doi: 10.1073/pnas.0703767104. Epub 2007 Sep 7.
The factors involved in the differentiation of memory CD4 T cells from naïve precursors are poorly understood. We developed a system to examine the effect of increased competition for antigen by CD4 T cells on the generation of memory in response to infection with a recombinant vesicular stomatitis virus. Competition was initially regulated by increasing the precursor frequency of adoptively transferred naïve T cell antigen receptor transgenic CD4 T cells. Despite robust proliferation at high precursor frequencies, memory CD4 T cells did not develop, whereas decreasing the input number of naïve CD4 T cells promoted memory development after infection. The lack of memory development was linked to reduced blastogenesis and poor effector cell induction, but not to initial recruitment or proliferation of antigen-specific CD4 T cells. To prove that availability of antigen alone could regulate memory CD4 T cell development, we used treatment with an mAb specific for the epitope recognized by the transferred CD4 T cells. At high doses, this mAb effectively inhibited the antigen-specific CD4 T cell response. However, at a very low dose of mAb, primary CD4 T cell expansion was unaffected, although memory development was dramatically reduced. Moreover, the induction of effector function was concomitantly inhibited. Thus, competition for antigen during CD4 T cell priming is a major contributing factor to the development of the memory CD4 T cell pool.
初始CD4 T细胞分化为记忆性CD4 T细胞所涉及的因素目前仍知之甚少。我们开发了一个系统，用于研究CD4 T细胞对抗原竞争增加对感染重组水疱性口炎病毒后记忆细胞生成的影响。竞争最初是通过增加过继转移的初始T细胞抗原受体转基因CD4 T细胞的前体频率来调节的。尽管在前体频率较高时细胞增殖强劲，但记忆性CD4 T细胞并未发育，而减少初始CD4 T细胞的输入数量则促进了感染后记忆细胞的发育。记忆细胞发育的缺失与增殖能力降低和效应细胞诱导不佳有关，但与抗原特异性CD4 T细胞的初始募集或增殖无关。为了证明仅抗原的可及性就能调节记忆性CD4 T细胞的发育，我们使用了针对过继转移的CD4 T细胞所识别表位的单克隆抗体进行处理。高剂量时，这种单克隆抗体有效抑制了抗原特异性CD4 T细胞反应。然而，在非常低剂量的单克隆抗体情况下，初始CD4 T细胞扩增未受影响，尽管记忆细胞发育显著减少。此外，效应功能的诱导也同时受到抑制。因此，CD4 T细胞启动过程中对抗原的竞争是记忆性CD4 T细胞库发育的一个主要促成因素。
