Journal
INTERNATIONAL IMMUNOPHARMACOLOGY
Volume 93, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.intimp.2021.107425
Keywords
Th17 cells; Cathepsin L; Autoimmune disorder
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Through bone marrow chimeras, researchers found that CtsL is involved in the pathogenicity of CD4 T cells in autoimmune diseases, but there is no defect in differentiation in vitro. In the experimental autoimmune encephalomyelitis (EAE) model, deficiency of CtsL significantly decreased the activation of pathogenic CD4 T cells.
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 naive 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-gamma 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.
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