The Clinical Significance of Hepatic CD69 ⁺ CD103 ⁺ CD8 ⁺ Resident‐Memory T Cells in Autoimmune Hepatitis

BACKGROUND AND AIMS: The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic. APPROACH AND RESULTS: We report herein that CD69(+)CD103(+)CD8(+) tissue-resident memory T cells (T-RM) are significantly increased in the liver of patients with AIH compared to chronic hepatitis B, NAFLD, and healthy control tissues. In addition, there was a significant statistical correlation between elevation of CD8(+) T-RM cells and AIH disease severity. Indeed, in patients with successful responses to immunosuppression, the frequencies of such hepatic CD8(+) T-RM cells decreased significantly. CD69(+)CD8(+) and CD69(+)CD103(+)CD8(+) T cells, also known as CD8(+) T-RM cells, reflect tissue residency and are well known to provide intense immune antigenic responses. Hence, it was particularly interesting that patients with AIH also manifest an elevated expression of IL-15 and TGF-beta on inflammatory cells, and extensive hepatic expression of E-cadherin; these factors likely contribute to the development and localization of CD8(+) T-RM cells. Based on these data and, in particular, the relationships between disease severity and CD8(+) T(RM )cells, we studied the mechanisms involved with glucocorticoid (GC) modulation of CD8(+) T-RM cell expansion. Our data reflect that GCs in vitro inhibit the expansion of CD8(+) T-RM cells induced by IL-15 and TGF-beta and with direct down-regulation of the nudear factor Blimpl of CD8(+) T-RM cells. CONCLUSIONS: Our data suggest that CD8(+) T-RM cells play a critical role in the pathogenesis of AIH, and GCs attenuate hepatic inflammation through direct inhibition of CD8(+) T(RM)( )cell expansion.