Differential expression of major histocompatibility complex class II genes on murine macrophages associated with T cell cytokine profile and protective/suppressive effects

Protective/suppressive major histocompatibility complex (MHC) class II alleles have been identified in humans and mice where they exert a disease-protective and immunosuppressive effect. Various modes of action have been proposed, among them differential expression of MHC class II genes in different types of antigen-presenting cells impacting on the T helper type 1 (Th1)–Th2 balance. To test this possibility, the expression of H-2 molecules from the four haplotypes H-2(b), H-2(d), H-2(k), and H-2(q) was determined on bone marrow-derived macrophages (BMDMs) and splenic B cells. The I-A(b) and I-E(k) molecules, both well characterized as protective/suppressive, are expressed at a high level on almost all CD11b(+) BMDMs for 5–8 days, after which expression slowly declines. In contrast, I-A(d), I-A(k), and I-A(q) expression is lower, peaks over a shorter period, and declines more rapidly. No differential expression could be detected on B cells. In addition, the differential MHC class II expression found on macrophages skews the cytokine response of T cells as shown by an in vitro restimulation assay with BMDMs as antigen-presenting cells. The results indicate that macrophages of the protective/suppressive haplotypes express MHC class II molecules at a high level and exert Th1 bias, whereas low-level expression favors a Th2 response. We suggest that the extent of expression of the class II gene gates the back signal from T cells and in this way controls the activity of macrophages. This effect mediated by polymorphic nonexon segments of MHC class II genes may play a role in determining disease susceptibility in humans and mice.

已在人类与小鼠中鉴定出兼具疾病保护与免疫抑制效应的保护性/抑制性主要组织相容性复合体（major histocompatibility complex, MHC）II类等位基因。目前已提出多种潜在作用机制，其中一类机制为：不同类型抗原呈递细胞中MHC II类基因的差异表达，可对辅助性T细胞1型（Th1）-Th2细胞平衡产生调控作用。为验证该假说，研究人员针对4种单体型H-2(b)、H-2(d)、H-2(k)与H-2(q)的H-2分子，分别在骨髓来源巨噬细胞（bone marrow-derived macrophages, BMDMs）与脾脏B细胞中的表达水平进行了检测。其中已被充分证实具备保护性/抑制性功能的I-A(b)与I-E(k)分子，可在几乎所有CD11b阳性BMDMs上呈高水平表达，持续时长为5至8天，随后表达水平缓慢下降。与之相比，I-A(d)、I-A(k)与I-A(q)的表达水平较低，其表达峰值持续时间更短，且下降速度更快。在脾脏B细胞中未检测到此类表达差异。此外，以BMDMs作为抗原呈递细胞的体外再刺激实验结果显示，巨噬细胞上的MHC II类差异表达会改变T细胞的细胞因子应答模式。研究结果表明，携带保护性/抑制性单体型的巨噬细胞会高水平表达MHC II类分子，并呈现Th1细胞偏向性；而低水平表达则更倾向于诱导Th2细胞应答。我们推测，II类基因的表达水平可作为调控阈值，介导T细胞向巨噬细胞传递的反向信号，进而调控巨噬细胞的活性。由MHC II类基因多态性非外显子区段介导的这一效应，可能在人类与小鼠的疾病易感性调控中发挥作用。