High-throughput sequencing reveals restricted TCR Vβ usage and public TCRβ clonotypes among pancreatic lymph node memory CD4(+) T cells and their involvement in autoimmune diabetes.
High-throughput sequencing reveals restricted TCR Vβ usage and public TCRβ clonotypes among pancreatic lymph node memory CD4(+) T cells and their involvement in autoimmune diabetes.
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DOI：
10.1016/j.molimm.2016.04.013
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发表时间：
2016-06
影响因子：
3.6
通讯作者：
Kumar V
中科院分区：
文献类型：
--
作者：
Marrero I;Aguilera C;Hamm DE;Quinn A;Kumar V
胰岛反应性记忆CD 4 + T细胞是1型糖尿病（T1 D）的一个基本特征，因为它们参与自发性疾病和胰岛移植后复发。在糖尿病患者的外周血中也显示了记忆T细胞的扩增和富集。在这里，我们使用高通量测序，研究了非肥胖糖尿病（NOD）小鼠胰腺淋巴结（PaLN）中记忆性CD 4 + T细胞TCRβ库的克隆多样性，并检查了它们与胰岛浸润记忆性CD 4 T细胞的克隆重叠。糖尿病前期和糖尿病NOD小鼠均表现出由表达TRBV 13 -2、TRBV 13 -1或TRBV 5基因片段的克隆主导的限制性TCRβ库。在PaLN和胰腺的记忆性CD 4库之间以及在糖尿病前期和糖尿病组之间存在有限程度的TCRβ重叠。然而，在几只个体动物中鉴定了公共TCRβ克隆型，其中一些具有与来自胰岛反应性T细胞的TCR相似的序列，表明其抗原驱动的扩增。此外，大多数公共克隆型表达TRBV 13 -2（Vβ8.2）基因片段。用来自TCR Vβ8.2链的免疫优势肽进行鼻内接种可预防糖尿病，表明Vβ8.2+ CD 4+记忆T细胞在T1 D中起关键作用。这些结果表明，携带有限显性TRBV基因的记忆性CD 4 + T细胞有助于自身免疫性糖尿病，并且可以潜在地靶向干预糖尿病。此外，我们的研究结果具有重要意义的公共T细胞克隆型的识别作为潜在的新的目标，在人类T1 D的免疫操作。
Islet-reactive memory CD4+ T cells are an essential feature of type 1 diabetes (T1D) as they are involved in both spontaneous disease and in its recurrence after islet transplantation. Expansion and enrichment of memory T cells have also been shown in the peripheral blood of diabetic patients. Here, using high-throughput sequencing, we investigated the clonal diversity of the TCRβ repertoire of memory CD4+ T cells in the pancreatic lymph nodes (PaLN) of non-obese diabetic (NOD) mice and examined their clonal overlap with islet-infiltrating memory CD4 T cells. Both prediabetic and diabetic NOD mice exhibited a restricted TCRβ repertoire dominated by clones expressing TRBV13-2, TRBV13-1 or TRBV5 gene segments. There is a limited degree of TCRβ overlap between the memory CD4 repertoire of PaLN and pancreas as well as between the prediabetic and diabetic group. However, public TCRβ clonotypes were identified across several individual animals, some of them with sequences similar to the TCRs from the islet-reactive T cells suggesting their antigen-driven expansion. Moreover, the majority of the public clonotypes expressed TRBV13-2 (Vβ8.2) gene segment. Nasal vaccination with an immunodominat peptide derived from the TCR Vβ8.2 chain led to protection from diabetes, suggesting a critical role for Vβ8.2+ CD4+ memory T cells in T1D. These results suggest that memory CD4+ T cells bearing limited dominant TRBV genes contribute to the autoimmune diabetes and can be potentially targeted for intervention in diabetes. Furthermore, our results have important implications for the identification of public T cell clonotypes as potential novel targets for immune manipulation in human T1D.
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影响因子：
56.9
作者：
Arstila, TP;Casrouge, A;Kourilsky, P
通讯作者：
Kourilsky, P
通过在胰腺淋巴结中发育调节的胰岛细胞抗原的发育表现来启动自身免疫性糖尿病。
DOI：
10.1084/jem.189.2.331
发表时间：
1999-01-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Höglund P;Mintern J;Waltzinger C;Heath W;Benoist C;Mathis D
通讯作者：
Mathis D
影响因子：
4.4
作者：
Estorninho, Megan;Gibson, Vivienne B.;Peakman, Mark
通讯作者：
Peakman, Mark
影响因子：
4.4
作者：
Klarenbeek, Paul L.;Tak, Paul P.;de Vries, Niek
通讯作者：
de Vries, Niek
影响因子：
4.4
作者：
DREXLER, K;BURTLES, S;HURTENBACH, U
通讯作者：
HURTENBACH, U