Regulatory T cells that co-express RORt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer
Regulatory T cells that co-express RORt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer
复制标题
DOI：
10.1080/2162402x.2015.1102828
复制
发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Aandahl, Einar M.
中科院分区：
文献类型：
--
作者：
Chellappa, Stalin;Hugenschmidt, Harald;Aandahl, Einar M.
胰腺导管腺癌（PDAC）被表达RORt和IL-17（T（H）17）的CD 4（+）T细胞高度浸润。来自肿瘤微环境的令人信服的证据表明，调节性T细胞（T-reg）有助于T（H）17介导的炎症。同时，PDAC患者的促炎细胞因子水平升高，可能导致T（H）17相关的功能可塑性T-reg。在这项研究中，我们调查了PDAC患者的表型和功能特性的T-reg。我们报道PDAC患者FOXP 3（+）T（reg）的频率升高，其仅发生在FOXP 3（+）RORt（+）T（reg）室中。FOXP 3（+）RORt（+）T（reg）保留FOXP 3（+）T（reg）标记，代表活化的亚群。RORt在T-reg中的表达可能指示向T（H）17细胞的表型转换。然而，FOXP 3（+）RORt（+）T（reg）产生T（H）17和T（H）2相关的促炎细胞因子，这与PDAC患者中升高的T（H）17和T（H）2免疫应答相对应。PDAC患者的FOXP 3（+）T（reg）和FOXP 3（+）RORt（+）T（reg）均强烈抑制T细胞免疫应答，但它们的抗炎特性受损。我们的结论是FOXP 3（+）RORt（+）T（reg）具有双重表型，具有促炎和免疫抑制活性，可能参与PDAC的发病机制。
Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4(+)T cells that express RORt and IL-17 (T(H)17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (T-reg) contribute to T(H)17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to T(H)17 associated functional plasticity in T-reg. In this study, we investigated the phenotype and functional properties of T-reg in patients with PDAC. We report that PDAC patients have elevated frequency of FOXP3(+)T(reg), which exclusively occurred within the FOXP3(+)RORt(+)T(reg) compartment. The FOXP3(+)RORt(+)T(reg) retained FOXP3(+)T(reg) markers and represented an activated subset. The expression of RORt in T-reg may indicate a phenotypic switch toward T(H)17 cells. However, the FOXP3(+)RORt(+)T(reg) produced both T(H)17 and T(H)2 associated pro-inflammatory cytokines, which corresponded with elevated T(H)17 and T(H)2 immune responses in PDAC patients. Both the FOXP3(+)T(reg) and FOXP3(+)RORt(+)T(reg) from PDAC patients strongly suppressed T cell immune responses, but they had impaired anti-inflammatory properties. We conclude that FOXP3(+)RORt(+)T(reg) have a dual phenotype with combined pro-inflammatory and immunosuppressive activity, which may be involved in the pathogenesis of PDAC.