Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Immunology. 2012 Aug;136(4):425-36. doi: 10.1111/j.1365-2567.2012.03599.x.
An understanding of factors controlling CD4 T-cell immunodominance is needed to pursue CD4 T-cell epitope-driven vaccine design, yet our understanding of this in humans is limited by the complexity of potential MHC class II molecule expression. In the studies described here, we took advantage of genetically restricted, well-defined mouse strains to better understand the effect of increasing MHC class II molecule diversity on the CD4 T-cell repertoire and the resulting anti-influenza immunodominance hierarchy. Interferon-γ ELISPOT assays were implemented to directly quantify CD4 T-cell responses to I-A(b) and I-A(s) restricted peptide epitopes following primary influenza virus infection in parental and F(1) hybrid strains. We found striking and asymmetric declines in the magnitude of many peptide-specific responses in F(1) animals. These declines could not be accounted for by the lower surface density of MHC class II on the cell or by antigen-presenting cells failing to stimulate T cells with lower avidity T-cell receptors. Given the large diversity of MHC class II expressed in humans, these findings have important implications for the rational design of peptide-based vaccines that are based on the premise that CD4 T-cell epitope specificity can be predicted by a simple cataloguing of an individual's MHC class II genotype.
为了追求基于 CD4 T 细胞表位的疫苗设计，需要了解控制 CD4 T 细胞免疫优势的因素，但由于潜在 MHC Ⅱ类分子表达的复杂性，我们对人类的这方面了解有限。在本文所描述的研究中，我们利用遗传限制的、明确的小鼠品系，更好地理解增加 MHC Ⅱ类分子多样性对 CD4 T 细胞库的影响，以及由此产生的抗流感免疫优势等级。干扰素-γ ELISPOT 检测被用来直接定量分析在原发性流感病毒感染后，亲本和 F1 杂交品系中 I-A(b)和 I-A(s)限制的肽表位的 CD4 T 细胞反应。我们发现，在 F1 动物中，许多肽特异性反应的强度都出现了惊人的、不对称的下降。这些下降不能用细胞上 MHC Ⅱ类分子的表面密度较低或抗原呈递细胞不能用较低亲和力的 T 细胞受体刺激 T 细胞来解释。考虑到人类表达的 MHC Ⅱ类分子的多样性很大，这些发现对基于肽的疫苗的合理设计具有重要意义，这些疫苗基于 CD4 T 细胞表位特异性可以通过简单地对个体的 MHC Ⅱ类基因型进行编目来预测的前提。
