T follicular helper (T FH ) cells play a crucial role in the development of long-lived, high-quality B cell responses after infection and vaccination. However, little is known about how antigen-specific T FH cells clonally evolve in response to complex pathogens and what guides the targeting of different epitopes. Here, we assessed the cell phenotype, clonal dynamics, and T cell receptor (TCR) specificity of human circulating T FH (cT FH ) cells during successive malaria immunizations with radiation-attenuated Plasmodium falciparum ( Pf ) sporozoites. Repeated parasite exposures induced a dynamic, polyclonal cT FH response with high frequency of cells specific to a small number of epitopes in Pf circumsporozoite protein (PfCSP), the primary sporozoite surface protein and well-defined vaccine target. Human leukocyte antigen (HLA) restrictions and differences in TCR generation probability were associated with differences in the epitope targeting frequency and indicated the potential of amino acids 311 to 333 in the Th2R/T* region as a T cell supertope. But most of vaccine-induced anti–amino acid 311 to 333 TCRs, including convergent TCRs with high sequence similarity, failed to tolerate natural polymorphisms in their target peptide sequence, thus demonstrating that the T FH cell response was limited to the vaccine strain. These data suggest that the high parasite diversity in endemic areas will limit boosting of the vaccine-induced T FH cell response by natural infections. Our findings may guide the further design of PfCSP-based malaria vaccines able to induce potent T helper cell responses for broad, long-lasting antibody responses.

中文翻译：

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人 T FH 细胞对恶性疟原虫 CSP 反应的克隆进化和 TCR 特异性

T 卵泡助手（T跳频) 细胞在感染和接种疫苗后长寿命、高质量 B 细胞反应的发展中起着至关重要的作用。然而，关于抗原特异性 T跳频细胞克隆进化以响应复杂的病原体以及引导不同表位靶向的因素。在这里，我们评估了人类循环 T 的细胞表型、克隆动力学和 T 细胞受体 (TCR) 特异性跳频(cT跳频) 细胞在连续疟疾免疫期间使用减毒辐射恶性疟原虫(磷) 子孢子。重复的寄生虫暴露诱导了动态的多克隆 cT跳频对少数表位特异的细胞的高频反应磷环子孢子蛋白 (PfCSP)，初级子孢子表面蛋白和明确的疫苗靶点。人类白细胞抗原 (HLA) 限制和 TCR 生成概率的差异与表位靶向频率的差异相关，并表明 Th2R/T* 区域中的氨基酸 311 至 333 作为 T 细胞超表位的潜力。但大多数疫苗诱导的抗氨基酸 311 至 333 TCR，包括具有高度序列相似性的收敛 TCR，不能耐受其靶肽序列中的天然多态性，从而证明 T跳频细胞反应仅限于疫苗株。这些数据表明，流行地区的高寄生虫多样性将限制疫苗诱导的 T跳频自然感染引起的细胞反应。我们的研究结果可能会指导进一步设计基于 PfCSP 的疟疾疫苗，该疫苗能够诱导有效的 T 辅助细胞反应以实现广泛、持久的抗体反应。