Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1202, USA.
Exp Hematol. 2011 Aug;39(8):837-49. doi: 10.1016/j.exphem.2011.05.005. Epub 2011 May 13.
To test the hypothesis that γ-interferon (IFN-γ) promotes major histocompatibility complex (MHC) class II expression on bone marrow (BM) cell targets that facilitate T-cell-mediated BM destruction in immune-mediated BM failure.
Allogeneic lymph node (LN) cells were infused into MHC- or minor histocompatibility antigen-mismatched hosts to induce BM failure. MHC class II and Fas expression and cell apoptosis were analyzed by flow cytometry. MHC class II-Fas colocalization was detected by ImageStream Imaging Flow Cytometry and other cell-to-cell associations were visualized by confocal microscopy. T-cell-mediated BM cell apoptosis and effects of IFN-γ on MHC class II-Fas colocalization on normal BM cells were studied using cell culture in vitro followed by conventional and imaging flow cytometry.
BM failure animals had significantly upregulated MHC class II expression on CD4(-)CD8(-)CD11b(-)CD45R(-) residual BM cells and significantly increased MHC class II-Fas colocalization on BM CD150(+) and CD34(+) hematopoietic cells. MHC class II(+)Fas(+) BM cells were closely associated with CD4(+) T cells in the BM of affected animals, and they were significantly more responsive to T-cell-mediated cell apoptosis relative to MHC class II(-)Fas(-) BM cells. Infusion of IFN-γ-deficient LN cells into minor histocompatibility antigen-mismatched recipients resulted in no MHC class II-Fas upregulation and no clinically overt BM failure. Treatment with recombinant IFN-γ significantly increased both MHC class II-Fas coexpression and colocalization on normal BM cells.
Elevation of the inflammatory cytokine IFN-γ-stimulated MHC class II expression and MHC class II-Fas colocalization, which may facilitate T-cell-mediated cell destruction.
检验以下假说，即 γ-干扰素（IFN-γ）促进主要组织相容性复合体（MHC）Ⅱ类在骨髓（BM）细胞靶标上的表达，从而促进免疫介导的 BM 衰竭中的 T 细胞介导的 BM 破坏。
将同种异体淋巴结（LN）细胞输注到 MHC 或次要组织相容性抗原错配的宿主中，以诱导 BM 衰竭。通过流式细胞术分析 MHC Ⅱ类和 Fas 的表达和细胞凋亡。通过 ImageStream 成像流式细胞术检测 MHC Ⅱ类-Fas 共定位，并通过共聚焦显微镜观察其他细胞间的关联。通过体外细胞培养研究 T 细胞介导的 BM 细胞凋亡以及 IFN-γ对正常 BM 细胞上 MHC Ⅱ类-Fas 共定位的影响，随后进行常规和成像流式细胞术分析。
BM 衰竭动物的 CD4(-)CD8(-)CD11b(-)CD45R(-)残留 BM 细胞上 MHC Ⅱ类的表达显著上调，BM CD150(+)和 CD34(+)造血细胞上 MHC Ⅱ类-Fas 的共定位显著增加。受影响动物 BM 中 MHC Ⅱ(+)Fas(+)BM 细胞与 CD4(+)T 细胞密切相关，与 MHC Ⅱ(-)Fas(-)BM 细胞相比，它们对 T 细胞介导的细胞凋亡更为敏感。将 IFN-γ 缺陷型 LN 细胞输注到次要组织相容性抗原错配的受者中，导致 MHC Ⅱ类-Fas 无上调且无临床明显的 BM 衰竭。用重组 IFN-γ治疗可显著增加正常 BM 细胞上 MHC Ⅱ-Fas 的共表达和共定位。
升高的炎症细胞因子 IFN-γ刺激 MHC Ⅱ类的表达和 MHC Ⅱ类-Fas 的共定位，可能促进 T 细胞介导的细胞破坏。
