Variation in CD8 T cell IFNγ differentiation to strains of Toxoplasma gondii is characterized by small effect QTLs with contribution from ROP16.
Variation in CD8 T cell IFNγ differentiation to strains of Toxoplasma gondii is characterized by small effect QTLs with contribution from ROP16.
复制标题
DOI：
10.3389/fcimb.2023.1130965
复制
发表时间：
2023
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
--
作者：
刚地弓形虫诱导强烈的CD8 T细胞反应，其特征是分泌IFNγ，促进宿主在感染期间的存活。刚地弓形虫克隆系菌株在体外启动CD8 T细胞IFNγ反应的差异很大，其中I型菌株是低诱导剂，而II型和III型菌株是高诱导剂。我们假设这种表型是由于多态的“CD8 T细胞反应调节器”（ROCTR）。因此，我们从克隆谱系株之间的遗传杂交中筛选F1后代来鉴定ROCTR。Naïve抗原特异性CD8 T细胞（T57）是从跨核小鼠中分离出来的，对内源性和空泡TGD057抗原具有特异性，我们测量了它们在弓形虫感染的巨噬细胞中被激活、转录Ifng和产生IFNγ的能力。遗传作图得到4个不相互作用的数量性状位点（QTL），对弓形虫染色体（chr） vib - viii， X和XII影响较小。这些基因座包含多个候选基因，其中ROP16 (chrvib - viii), GRA35 (chrX), TgNSM （chrX）和一对未表征的NTPases （chrXII）突出显示，其位点在I型RH背景中显着截断。虽然X和XII候选染色体没有证据表明可以调节CD8 T细胞的IFNγ反应，但ROP16的I型变体在T细胞激活后早期降低了IFNγ的转录。在我们寻找ROCTR的过程中，我们还注意到寄生物液泡膜（PVM）致密颗粒（GRAs）靶向因子GRA43抑制了应答，这表明PVM相关的GRAs对CD8 T细胞活化很重要。此外，巨噬细胞中RIPK3的表达是CD8 T细胞IFNγ分化的绝对必要条件，这与T细胞对弓形虫免疫的坏死坏死途径有关。总的来说，我们的数据表明，虽然CD8 T细胞对弓形虫菌株产生的IFNγ变化很大，但它不是由单一的多态性控制的。然而，在分化过程的早期，ROP16的多态性可以调节应答CD8 T细胞对IFNγ产生的承诺，这可能与弓形虫的免疫有关。
Toxoplasma gondii induces a strong CD8 T cell response characterized by the secretion of IFNγ that promotes host survival during infection. The initiation of CD8 T cell IFNγ responses in vitro differs widely between clonal lineage strains of T. gondii, in which type I strains are low inducers, while types II and III strains are high inducers. We hypothesized this phenotype is due to a polymorphic “Regulator Of CD8 T cell Response” (ROCTR). Therefore, we screened F1 progeny from genetic crosses between the clonal lineage strains to identify ROCTR. Naïve antigen-specific CD8 T cells (T57) isolated from transnuclear mice, which are specific for the endogenous and vacuolar TGD057 antigen, were measured for their ability to become activated, transcribe Ifng and produce IFNγ in response to T. gondii infected macrophages. Genetic mapping returned four non-interacting quantitative trait loci (QTL) with small effect on T. gondii chromosomes (chr) VIIb-VIII, X and XII. These loci encompass multiple gene candidates highlighted by ROP16 (chrVIIb-VIII), GRA35 (chrX), TgNSM (chrX), and a pair of uncharacterized NTPases (chrXII), whose locus we report to be significantly truncated in the type I RH background. Although none of the chromosome X and XII candidates bore evidence for regulating CD8 T cell IFNγ responses, type I variants of ROP16 lowered Ifng transcription early after T cell activation. During our search for ROCTR, we also noted the parasitophorous vacuole membrane (PVM) targeting factor for dense granules (GRAs), GRA43, repressed the response suggesting PVM-associated GRAs are important for CD8 T cell activation. Furthermore, RIPK3 expression in macrophages was an absolute requirement for CD8 T cell IFNγ differentiation implicating the necroptosis pathway in T cell immunity to T. gondii. Collectively, our data suggest that while CD8 T cell IFNγ production to T. gondii strains vary dramatically, it is not controlled by a single polymorphism with strong effect. However, early in the differentiation process, polymorphisms in ROP16 can regulate commitment of responding CD8 T cells to IFNγ production which may have bearing on immunity to T. gondii.
影响因子：
7.2
作者：
Michaud M;Sukkurwala AQ;Martins I;Shen S;Zitvogel L;Kroemer G
通讯作者：
Kroemer G