ITK independent development of Th17 responses during hypersensitivity pneumonitis driven lung inflammation.
ITK independent development of Th17 responses during hypersensitivity pneumonitis driven lung inflammation.
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DOI：
10.1038/s42003-022-03109-1
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发表时间：
2022-02-24
影响因子：
5.9
通讯作者：
August A
中科院分区：
文献类型：
--
作者：
Elmore J;Carter C;Redko A;Koylass N;Bennett A;Mead M;Ocasio-Rivera M;Huang W;Singh A;August A
T辅助17（Th 17）细胞在特定环境存在下响应于T细胞受体信号（TCR）而发育，并产生炎性细胞因子IL 17 A。这些细胞与许多炎性疾病有关，并代表了改善此类疾病的潜在靶点。激酶ITK是TCR信号的关键调节因子，已显示其是Th 17细胞发育所需的。然而，我们在此表明，由直枝多孢菌（SR）诱导的过敏性肺炎（SR-HP）诱导的肺部炎症导致中性粒细胞非依赖性和ITK非依赖性Th 17应答，尽管ITK信号是γδ T细胞产生IL 17 A所必需的。对所得的ITK非依赖性Th 17细胞的转录组学分析表明，SR-HP诱导的外源性炎症信号可以覆盖ITK下游的内源性T细胞信号，以在不存在ITK的情况下拯救Th 17应答。这些发现表明，药物靶向ITK以抑制Th 17应答的能力可能取决于炎症的类型。激酶Itk通常是产生IL-17的CD 4辅助性T（Th）17细胞分化所需的，然而，Elmore，Carter等人现在报道，在直枝多孢菌诱导的过敏性肺炎中，Itk可以在Th 17分化期间被绕过。这项研究表明，一些炎症信号可以覆盖正常的T细胞活化和分化途径。
T helper 17 (Th17) cells develop in response to T cell receptor signals (TCR) in the presence of specific environments, and produce the inflammatory cytokine IL17A. These cells have been implicated in a number of inflammatory diseases and represent a potential target for ameliorating such diseases. The kinase ITK, a critical regulator of TCR signals, has been shown to be required for the development of Th17 cells. However, we show here that lung inflammation induced by Saccharopolyspora rectivirgula (SR) induced Hypersensitivity pneumonitis (SR-HP) results in a neutrophil independent, and ITK independent Th17 responses, although ITK signals are required for γδ T cell production of IL17A. Transcriptomic analysis of resultant ITK independent Th17 cells suggest that the SR-HP-induced extrinsic inflammatory signals may override intrinsic T cell signals downstream of ITK to rescue Th17 responses in the absence of ITK. These findings suggest that the ability to pharmaceutically target ITK to suppress Th17 responses may be dependent on the type of inflammation. The kinase Itk is normally required for differentiation of IL-17-producing CD4 T-helper (Th)17 cells however, Elmore, Carter et al. now report that Itk can be bypassed during Th17 differentiation in Saccharopolyspora rectivirgula induced hypersensitivity pneumonitis. This study suggests that some inflammatory signals can override normal T cell activation and differentiation pathways.