CTLA-4-Ig internalizes CD80 in fibroblast-like synoviocytes from chronic inflammatory arthritis mouse model

CD80 interact with CD28 and CTLA-4 on antigen-presenting cells, and function in the co-stimulatory signaling that regulates T cell activity. CTLA-4-Ig is used to treat RA by blocking co-stimulatory signaling. Chronic inflammatory arthritis was induced in D1BC mice using low-dose arthritogenic antigens and treated with CTLA-4-Ig. We performed histopathology of the joints and lymph nodes, serological examination for rheumatoid factors, and flow cytometric analysis of isolated synovial cells, including CD45(−) FLSs and CD45(+) synovial macrophages. CTLA-4-Ig treatment ameliorated the chronic inflammatory polyarthritis. There was a decrease in the number of infiltrating lymphoid cells in the joints as well as in the levels of RF-IgG associated with a decrease in the number of B cells in the lymph nodes; more than 15% of CD45(−) FLSs expressed CD80, and a small number of them expressed PD-L1, indicating the presence of PD-L1/CD80 cis-heterodimers in these cells. CTLA-4-Ig internalized CD80, but not PD-L1, in isolated synovial cells. Gene ontology analysis revealed that CTLA-4-Ig internalization did not significantly alter the expression of inflammation-related genes. The therapeutic effect of CTLA-4-Ig appears to extend beyond the lymph nodes into the inflamed synovial compartment through the synergistic inactivation of T cells by the CD80 and PD-L1 axes.