An enhanced level of LAMP-2A participates in CD4(+)T cell hyperactivity in patients with primary biliary cholangitis

BACKGROUND: Primary biliary cholangitis (PBC) is an immune-mediated chronic cholestasis, in which T cell homeostasis plays an important role. Lysosomal-associated membrane protein 2 isoform A (LAMP-2A) has been implicated in the regulation of CD4(+)T cell responses. METHODS: We comprehensively evaluated the immunobiology of CD4(+)T cells in patients with PBC (PBC, n=42), chronic hepatitis B (CHB, n=20), and healthy control subjects (HC, n=20) by flow cytometry including activation status and LAMP-2A expression. Additionally, we investigated the activation responses of PBC-naïve CD4(+)T cells by stimulation in vitro and tested the changes caused by deleting the gene encoding LAMP-2A. RESULTS: Firstly, we found an increased activation status of circulating CD4(+)T cells from PBC patients compared to the HC subjects, and PBC-naïve CD4(+)T cells showed enhanced responses after stimulation in vitro. Secondly, PBC-naïve CD4(+)T cells expressed a significantly higher level of LAMP-2A compared to the HC and CHB groups [PBC vs. HC, 1,954.74 (1,254.28–3,057.14) vs. 1,542.12 (961.18–2,277.98), P=0.03; vs. CHB, 1,153.59 (726.87–1,275.48), P=0.02], and the overreactions of PBC-naïve CD4(+)T cells could be reversed by interfering with LAMP-2A expression in vitro. Thirdly, the LAMP-2A expression level of PBC-naïve CD4(+)T cells was related to disease severity and drug response. CONCLUSIONS: An abnormally increased LAMP-2A expression of PBC-naïve CD4(+)T cells might be related to excessive activation responses. LAMP-2A could be a novel therapeutic target for the treatment of PBC by reversing excessive responses and consequently reducing biliary injury.