Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Anaesthesia, Harvard Medical School, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Anaesthesia, Harvard Medical School, Boston, MA 02115, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
Int Immunopharmacol. 2021 Apr;93:107425. doi: 10.1016/j.intimp.2021.107425. Epub 2021 Feb 1.
Previously we reported that IL-17-producing CD4 T cells (Th17) were increased in mice lacking the protease inhibitor SerpinB1 and several SerpinB1-inhibitable cysteine cathepsins were induced in the Th17 cells, most prominently cathepsin L (CtsL). Since CtsL also mediates invariant chain processing in thymic epithelial cells, deficiency of CtsL leads to impaired CD4 T cell thymic selection, which hinders the direct investigation of CD4 T cells in CtsL mouse. In the current study, through transplanting the CtsL bone marrow into lethally irradiated CtsL-sufficient Rag mice (bone marrow chimeras), we reconstituted the immune system of CtsL chimeric mice, which possessed normal CD4 T cell development and allowed us to study the intrinsic role of CtsL in CD4 T cells in Th17 cell-driven autoimmune diseases. Surprisingly, we found that CtsL CD4 T cells had no defects in differentiation of naïve CD4 T cells into Th1, Treg and Th17 cells in vitro. However, in vivo, in experimental autoimmune encephalomyelitis (EAE) model, deficiency of CtsL significantly decreased the activation of IL-17, GM-CSF and IFN-γ producing pathogenic CD4 T cells. Compared with wild type (wt) controls, CtsL CD4 T cells were also less accumulated in the spinal cord in EAE. Thus, for the first time, our study provided the direct in vivo evidence that CtsL was involved in CD4 T cells acquiring pathogenicity in the autoimmune disease.
先前我们报道称，缺乏丝氨酸蛋白酶抑制剂 SerpinB1 的小鼠体内会增加产生白细胞介素 17（IL-17）的 CD4 T 细胞（Th17），并且 Th17 细胞中会诱导多种 SerpinB1 抑制的半胱氨酸组织蛋白酶，其中最主要的是组织蛋白酶 L（CtsL）。由于 CtsL 还介导了胸腺上皮细胞中不变链的加工，因此 CtsL 的缺乏会导致 CD4 T 细胞胸腺选择受损，这阻碍了对 CtsL 缺陷型小鼠 CD4 T 细胞的直接研究。在本研究中，我们通过将 CtsL 缺陷型骨髓移植到致死性辐照的 CtsL 充足 Rag 小鼠（骨髓嵌合体）中，重建了 CtsL 嵌合小鼠的免疫系统，使其具有正常的 CD4 T 细胞发育，并使我们能够研究 CtsL 在 Th17 细胞驱动的自身免疫性疾病中对 CD4 T 细胞的内在作用。令人惊讶的是，我们发现 CtsL 缺陷型 CD4 T 细胞在体外将初始 CD4 T 细胞分化为 Th1、Treg 和 Th17 细胞的过程中没有缺陷。然而，在体内实验性自身免疫性脑脊髓炎（EAE）模型中，CtsL 的缺乏显著降低了产生 IL-17、GM-CSF 和 IFN-γ的致病性 CD4 T 细胞的激活。与野生型（wt）对照相比，CtsL 缺陷型 CD4 T 细胞在 EAE 中也较少积累于脊髓。因此，我们的研究首次提供了直接的体内证据，表明 CtsL 参与了 CD4 T 细胞在自身免疫性疾病中获得致病性。
