BTLA调控CTL细胞命运的分子机制

Clinical Cancer Research

2017-07-28Article

9.619

影响因子

原标题:接触抗原后BTLA在控制CD8+ T细胞命运方面发挥多种作用

① 单细胞分析、反相蛋白分析、抗原特异性免疫模型、患者来源异种移植瘤模型,以自体肿瘤浸润性淋巴细胞(TIL)处理;② CD8+BTLA- TIL在体内不能控制肿瘤的生长,CD8+BTLA+ TIL及抗原特异性CD8+BTLA- T细胞疫苗应答缺陷;③ 杀伤肿瘤靶点及提高“连环杀伤”力之后,CD8+BTLA+ TIL改善生存;④ 通过提高IL-2分泌、TCR刺激后活化Src,Grb2介导共刺激功能;⑤ BTLA单一分子提供共刺激和共抑制信号,激活CD8+T细胞,延长生存期,发挥功能性回忆应答。

黑色素瘤 肿瘤浸润淋巴细胞 B和T淋巴细胞弱化因子 T细胞生存 肿瘤控制

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Title:
Multifaceted role of BTLA in the control of CD8+ T cell fate after antigen encounter

DOI:
10.1158/1078-0432.CCR-16-1217

Abstract & Authors展开

Abstract:
Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40-50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte attenuator) expression on transferred CD8(+) TIL was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8(+)BTLA(+)TIL subset and define the contribution of the Grb2 motif of BTLA in T cell co-stimulation. <br /><br />Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8(+) TIL and mouse CD8(+) T cells. Functional assays were used including single cell analysis, Reverse Phase Protein Array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as Patient-Derived Xenograft (PDX) model using Immunodeficient NOD-scid IL2Rgamma(null) (NSG) tumor-bearing mice treated with autologous TIL.<br /> <p>Results: CD8(+)BTLA(-) TIL could not control tumor growth in vivo as well as their BTLA(+) counterpart and antigen-specific CD8(+)BTLA(-) T cells had impaired recall response to a vaccine. However CD8(+)BTLA(+) TIL displayed improved survival following the killing of a tumor target and heightened "serial killing" capacity. Using mutants of BTLA signaling motifs we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation. <br /><br />Conclusions:Our data portrays BTLA as a molecule with the singular ability to provide both co-stimulatory and co-inhibitory signals to activated CD8(+) T cells, resulting in extended survival, improved tumor control and the development of a functional recall response.

All Authors:
Krit Ritthipichai,Cara Haymaker,Melisa Martinez-Paniagua,Andrew Aschenbrenner,Xiaohui Yi,Minying Zhang,Charuta Kale,Yared Hailemichael,Willem W Overwijk,Luis Vence,Jason Roszik,Navin Varadarajan,Roza Nurieva,Laszlo G Radvanyi,Patrick Hwu,Chantale Bernatchez

First Authors:
Krit Ritthipichai

Correspondence:
Chantale Bernatchez

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