CD8 T cell-mediated lung damage in response to the extracellular pathogen Pneumocystis is dependent on MHC class I expression by radiation-resistant lung cells
CD8 T cell-mediated lung damage in response to the extracellular pathogen Pneumocystis is dependent on MHC class I expression by radiation-resistant lung cells
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DOI：
10.4049/jimmunol.175.12.8271
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发表时间：
2005-12-15
影响因子：
4.4
通讯作者：
Harmsen, A
中科院分区：
文献类型：
--
作者：
Meissner, NN;Lund, FE;Harmsen, A
肺囊虫，一种真菌，细胞外病原体引起严重免疫缺陷患者危及生命的肺炎。在缺乏CD4 T细胞的情况下，肺囊虫感染导致大量CD8 T细胞涌入肺肺泡和肺间质。这种反应导致以低pO(2)和白蛋白渗漏到支气管肺泡灌洗液为特征的肺损伤，类似于其他CD8 T细胞介导的间质性肺疾病。这种细胞外病原体是如何引起CD8 T细胞反应的尚不清楚，我们研究的目的是确定募集的CD8 T细胞的Ag特异性，并确定MHC I类（MHC 1）表达是否是启动肺损伤所必需的。通过使用多克隆野生型CD8 T细胞或转基因流感病毒特异性CD8 T细胞的过继T细胞转移模型，我们发现CD8 T细胞募集是ag特异性的，并且需要肺囊虫病原体的持续存在。以rag1和β(2)-微球蛋白缺陷小鼠为宿主的骨髓嵌合体实验表明，肺非骨髓源性细胞需要MHC I表达。这表明肺囊虫抗原是由非骨髓来源的肺细胞直接加工的，或者是由肺特异性自身抗原诱发的肺损伤。使用穿孔素、Fas和ifn - γ缺乏的动物，我们发现这些分子并不直接参与cd8介导的肺损伤。然而，CD8 T细胞介导的肺损伤是ag特异性的，是由肺中表达MHC i的非骨髓来源细胞诱导的，并且依赖于活肺囊虫的持续存在。
Pneumocystis, a fungal, extracellular pathogen causes a life-threatening pneumonia in patients with severe immunodeficiencies. In the absence of CD4 T cells, Pneumocystis infection results in vigorous CD8 T cell influx into the alveolar and interstitial spaces of the lung. This response results in lung damage characterized by low pO(2) and albumin leakage into the bronchoalveolar lavage fluid similar to other CD8 T cell-mediated interstitial lung diseases. How this extracellular pathogen elicits a CD8 T cell response is not clear, and it was the aim of our study to determine the Ag specificity of the recruited CD8 T cells and to determine whether MHC class I (MHC 1) expression was necessary to initiate lung damage. Using an adoptive T cell-transfer model with either polyclonal wild-type CD8 T cells or transgenic influenza virus-specific CD8 T cells we found that CD8 T cell recruitment is Ag-specific and requires the continuous presence of the Pneumocystis pathogen. Bone marrow chimera experiments using Rag-1 and beta(2)-microglobulin-deficient mice as hosts demonstrated a requirement for MHC I expression on nonbone marrow-derived cells of the lung. This suggests either direct processing of Pneumocystis Ags by nonbone marrow-derived cells of the lung or the induction of lung damage triggered by a lung-specific autoantigen. Using perforin-, Fas-, and IFN-gamma-deficient animals, we showed that these molecules are not directly involved in the CD8-mediated lung damage. However, CD8 T cell-mediated lung damage is Ag-specific is induced by a MHC I-expressing nonbone marrow-derived cell in the lung and is dependent on the continued presence of live Pneumocystis.