B cells drive CCR5⁺CD4⁺ tissue-resident memory T-cell cytotoxicity via IL-15Rα-IL-15 signaling in primary biliary...

IL-15Rα mediates immune responses by binding and trans-presenting IL-15 to tissue-resident memory T (T_RM) cells, enabling sustained activation. Given the pivotal role of IL-15Rα/IL-15 signaling in autoimmune diseases, elucidating its organ-specific expression and pathogenic functions in primary biliary cholangitis (PBC) remains crucial.

Immunohistochemical staining was performed on liver tissues from healthy controls (n = 10) and patients with PBC (n = 94), autoimmune hepatitis (n = 32), chronic hepatitis B (n = 10), and metabolic dysfunction-associated steatohepatitis (n = 7) to assess IL-15Rα expression. Flow cytometric analysis was used to characterize intrahepatic IL-15Rα⁺ B cells and CD4⁺ T_RM cells. RNA sequencing was employed to delineate the transcriptomic signatures of in vitro-induced B cells and intrahepatic leukocytes. A cholangiocyte organoid co-culture system was employed to assess T_RM cell cytotoxicity. Moreover, dnTGFβRII mice treated with an anti-IL-15/IL-15Rα monoclonal antibody were used for in vivo validation.

IL-15Rα⁺ cells were significantly increased in the livers of patients with PBC, were primarily concentrated within the plasmablast B-cell population, and positively correlated with the severity of hepatic inflammation. IL-15Rα⁺ B cells, enriched around bile ducts in PBC livers, secrete CCL3 to recruit CCR5⁺CD4⁺ T_RM cells, enhancing their effector functions via IL-15Rα/IL-15 signaling. Notably, CCR5⁺CD4⁺ T_RM cells drive cholangiocyte pyroptosis through granzyme A-mediated gasdermin B cleavage. Furthermore, blockade of IL-15Rα/IL-15 signaling ameliorates liver injury in PBC mouse models.

Our findings reveal an important pathogenic mechanism in PBC wherein IL-15Rα⁺ B cells contribute to biliary injury by activating CCR5⁺CD4⁺ T_RM cells. This mechanism likely works in concert with other immune effector pathways in driving disease progression.

This study reveals that IL-15Rα-expressing B cells manifest a pro-inflammatory phenotype and promote biliary injury by impairing immune homeostasis through aberrant activation of tissue-resident memory T cells during primary biliary cholangitis progression. Although we now offer a new paradigm explaining how IL-15 trans-presentation is regulated in a B cell-dependent manner in primary biliary cholangitis, the regulatory effects of IL-15Rα/IL-15 signaling on other chronic liver diseases remain to be further elucidated.