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. 2017 Jul 21;7(1):6172.
doi: 10.1038/s41598-017-06352-3.

Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity

Femke Stelma  1   2 , Annikki de Niet  1   2 , Marjan J Sinnige  2 , Karel A van Dort  2 , Klaas P J M van Gisbergen  3 , Joanne Verheij  4 , Ester M M van Leeuwen  2 , Neeltje A Kootstra  2 , Hendrik W Reesink  5   6
Affiliations

Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity

Femke Stelma (V体育2025版) et al. Sci Rep. .

Abstract

Tissue resident memory T cells (TRM) have been identified in various tissues, however human liver TRM to date remain unidentified. TRM can be recognized by CD69 and/or CD103 expression and may play a role in the pathology of chronic hepatitis B (CHB) and hepatitis C virus infection (CHC). Liver and paired blood mononuclear cells from 17 patients (including 4 CHB and 6 CHC patients) were isolated and CD8+ T cells were comprehensively analysed by flowcytometry, immunohistochemistry and qPCR VSports手机版. The majority of intrahepatic CD8+ T cells expressed CD69, a marker used to identify TRM, of which a subset co-expressed CD103. CD69 + CD8+ T cells expressed low levels of S1PR1 and KLF2 and a large proportion (>90%) was CXCR6+, resembling liver TRM in mice and liver resident NK cells in human. Cytotoxic proteins were only expressed in a small fraction of liver CD69 + CD8+ T cells in patients without viral hepatitis, however, in livers from CHB patients more CD69 + CD8+ T cells were granzyme B+. In CHC patients, less intrahepatic CD69 + CD8+ T cells were Hobit+ as compared to CHB and control patients. Intrahepatic CD69 + CD8+ T cells likely TRM which have a reduced cytolytic potential. In patients with chronic viral hepatitis TRM have a distinct phenotype. .

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Conflict of interest statement

Hendrik W. Reesink serves as a consultant for AbbVie, Alnylam, Bristol Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck, PRA International, Regulus, Replicor, Roche and R-Pharm and received grant/research support from AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Janssen-Cilag, Merck, PRA International, Regulus, Replicor and Roche. All other authors: None declared V体育安卓版.

Figures

Figure 1
Figure 1
(a) Frequency of CD8+ and CD4+ T cells as a percentage of total CD3+ lymphocytes was compared in control blood and liver (n = 7). Statistical analyses; paired t-test. (b) Frequency of CD69+ and CD103+ as a percentage of total CD8+ T cells in blood and liver. Statistical analyses; paired t-test. (c) Representative flow cytometry plots showing CD69 and CD103 expression, gated on CD8 + CD3+ positive lymphocytes. (d) Paraffin embedded formalin-fixed sections of control livers (n = 3)(tumor-free tissue was used) were stained using sequential immunohistochemistry. An immunohistochemical staining of CD69 is shown with a portal field (*) and a central vein (#), and a portal field with co-localization of CD69 + CD8 + CD3+ lymphocytes (filled arrow) and CD69 + CD103 + CD8 + CD3 + lymphocytes (open arrow). Original magnification: 20x. (e) Relative expression of S1PR1 and transcription factor KLF2 in sorted CD69 + and CD69-CD8+ T cells from the liver (n = 6). Bars indicate median. Statistical analyses; Wilcoxon signed rank test. (f) Frequency of CXCR6+ T cells as a percentage of total CD8+ T cells in blood, liver CD69+ and liver CD69-CD8+ T cells. Statistical analyses; paired t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
Figure 2
Figure 2
Frequency of HLA-DR + CD38+ double positive (a) and Ki67 (b) positive cells as a percentage of CD8+ T cells and gMFI of PD-1 (c) in control blood vs. liver (CD69+ and CD69-) CD8+ T cells. Statistical analyses; paired t-test. **p < 0.01. (d) Relative expression of Nur77 in sorted CD69+ and CD69-CD8+ T cells from the liver (n = 6, one CD69+ sample was unavailable). Bars indicate median. Statistical analyses; Wilcoxon signed rank test. Abbreviations: ns, non-significant.
Figure 3
Figure 3
(a) Representative flow cytometry plots showing CD27 and CD45RA expression with gates indicating effector memory (TEFF, CD45RA ± CD27−), memory (TMEM, CD45RA-CD27+) and naïve (CD45RA + CD27 + ) CD8+ T cells in control blood and liver (CD69+ and CD69−). (b) Frequency of TEFF, TMEM and naïve CD8+ T cells as a percentage of total CD8+ T lymphocytes in control blood and liver (CD69+ and CD69−). Bars indicate mean. Statistical analyses; paired t-test *p < 0.05, **p < 0.01, ****p < 0.0001. Abbreviations: ns, non-significant.
Figure 4
Figure 4
Frequency of perforin+, granzyme B+, Tbethi, Hobit+ and Eomes+ cells as a percentage of CD8+ TEFF (a) and TMEM (b) in control blood and liver (CD69+ and CD69−). Statistical analyses; paired t-test. (c) Representative FACS staining and gating for perforin, granzyme B, Eomes and T-bet in blood and liver CD69 + ad CD69- TEFF and TMEM cells. Statistical analyses; paired t-test. (d) Relative expression of cytokines interferon-γ (IFNγ), tumor necrosis factor-α (TNFα) and macrophage inflammatory protein 1β (MIP-1β) in sorted CD69+ and CD69-CD8+ T cells from control livers. Bars indicate median. Statistical analyses; Wilcoxon signed rank test. *p < 0.05, **p < 0.01, ***p < 0.001 ****p < 0.0001. Abbreviations: ns, non-significant.
Figure 5
Figure 5
(a) Frequency of CD8+ and CD4+ T cells as a percentage of total CD3+ T lymphocytes in control (ctrl, n = 7), CHB infected (HBV, n = 3–4) and CHC infected (HCV, n = 5–6) livers (number of samples depending on sample availability). Bars indicate median. Statistical analyses; Mann-whitney test. (b) Frequency of CD69+ and CD103+ as a percentage of total CD8+ T lymphocytes in control, HBV and HCV livers. Bars indicate median. Statistical analyses; Mann-whitney test. Frequency of perforin+ (c), granzyme B+ (d) and Hobit+ (e) CD8+ T cells as a percentage of intrahepatic CD69 + CD8+ TEFF (upper graphs) and TMEM (lower graphs). Bars indicate median. Statistical analyses; Mann-whitney test. *p < 0.05, **p < 0.01.
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