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

Abstract

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 TGFβ 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 TGFβ and with direct down-regulation of the nuclear factor Blimp1 of CD8 + T RM cells.

The Roles of Tissue-Resident Memory T Cells in Lung Diseases

“…In addition to the protective roles against diseases, evidence suggests that T RM cells also become activated after sensitization to self-antigens. Aberrantly activated T RM cells can induce autoimmune disorders, such as autoimmune hepatitis and psoriasis (4,14). In the respiratory system, T RM specifically activated by environmental allergens might underlie the development and worsening of allergic asthma and other airway diseases (15)(16)(17)(18).…”

Regulation of Progression and Resolution of Liver Fibrosis by Immune Cells

“…Further studies are needed to elucidate the mechanisms underlying tissue-resident CD8 T cell–specific functions. Recent reports have also revealed that CD69+ CD103+ CD8 Trm-like cells accumulate locally in the liver in AIH 56 and in PSC. 57 Among Trm cells, the frequency of Trm-like phenotypes is higher in CD103+ CD69+ CD8 T cells around the bile duct than in CD69+ CD8 T cells in the liver tissue.…”

Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma

“…According to the procedure described previously ( 27 ), formalin-fixed, paraffin-embedded liver tissues were used for immunohistochemistry (IHC) and immunofluorescence with the primary antibodies targeting at CD103, CD8, TGF-β, IL-15 (all anti-human, ab129202, ab17147, ab170874, ab55276, Abcam, Cambridge, United Kingdom), and FGL1 (anti-human, ab275091, Abcam; anti-mouse, 16000-1-AP, Proteintech, San Diego, CA, USA). Then information of antibodies could be found in the Supplementary table .…”

“…The flow cytometric was conducted as reported previously ( 27 ). For surface staining, the cells were cultured with antibodies specific for human cell surface markers CD3, CD4, CD8, CD103, CD69, LAG-3, PD-1, TIM-3, and CTLA-4 (564713, 564724,564116, 350225, 557745, 565775, 329920,…”