Institute of Ecology and Evolution, University of Oregon, Eugene, OR 97403, USA.
Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR 97403, USA.
Mol Biol Evol. 2021 May 19;38(6):2273-2284. doi: 10.1093/molbev/msab022.
Molecular studies of host-pathogen evolution have largely focused on the consequences of variation at protein-protein interaction surfaces. The potential for other microbe-associated macromolecules to promote arms race dynamics with host factors remains unclear. The cluster of differentiation 1 (CD1) family of vertebrate cell surface receptors plays a crucial role in adaptive immunity through binding and presentation of lipid antigens to T-cells. Although CD1 proteins present a variety of endogenous and microbial lipids to various T-cell types, they are less diverse within vertebrate populations than the related major histocompatibility complex (MHC) molecules. We discovered that CD1 genes exhibit a high level of divergence between simian primate species, altering predicted lipid-binding properties and T-cell receptor interactions. These findings suggest that lipid-protein conflicts have shaped CD1 genetic variation during primate evolution. Consistent with this hypothesis, multiple primate CD1 family proteins exhibit signatures of repeated positive selection at surfaces impacting antigen presentation, binding pocket morphology, and T-cell receptor accessibility. Using a molecular modeling approach, we observe that interspecies variation as well as single mutations at rapidly-evolving sites in CD1a drastically alter predicted lipid binding and structural features of the T-cell recognition surface. We further show that alterations in both endogenous and microbial lipid-binding affinities influence the ability of CD1a to undergo antigen swapping required for T-cell activation. Together these findings establish lipid-protein interactions as a critical force of host-pathogen conflict and inform potential strategies for lipid-based vaccine development.
宿主-病原体进化的分子研究主要集中在蛋白质-蛋白质相互作用表面变异的后果上。其他微生物相关的大分子是否有可能与宿主因子一起促进军备竞赛动态尚不清楚。脊椎动物细胞表面受体的分化簇 1 (CD1) 家族通过与 T 细胞结合和呈递脂质抗原，在适应性免疫中发挥关键作用。虽然 CD1 蛋白将各种内源性和微生物脂质呈递给各种 T 细胞类型，但它们在脊椎动物群体中的多样性低于相关的主要组织相容性复合体 (MHC) 分子。我们发现 CD1 基因在灵长类物种之间存在高度的分化，改变了预测的脂质结合特性和 T 细胞受体相互作用。这些发现表明，脂质-蛋白冲突在灵长类动物进化过程中塑造了 CD1 基因的变异。与这一假设一致的是，多种灵长类 CD1 家族蛋白在影响抗原呈递、结合口袋形态和 T 细胞受体可及性的表面上表现出重复正选择的特征。使用分子建模方法，我们观察到种间变异以及 CD1a 中快速进化位点的单个突变极大地改变了预测的脂质结合和 T 细胞识别表面的结构特征。我们进一步表明，内源性和微生物脂质结合亲和力的改变都会影响 CD1a 进行抗原交换的能力，而抗原交换是 T 细胞激活所必需的。这些发现共同确立了脂质-蛋白相互作用是宿主-病原体冲突的关键力量，并为基于脂质的疫苗开发提供了潜在策略。
