SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis

Abstract

Background & aims: Autoimmune hepatitis episodes have been described following SARS-CoV-2 infection and vaccination but their pathophysiology remains unclear. Herein, we report the case of a 52-year-old male, presenting with bimodal episodes of acute hepatitis, each occurring 2-3 weeks after BNT162b2 mRNA vaccination. We sought to identify the underlying immune correlates. The patient received oral budesonide, relapsed, but achieved remission under systemic steroids.

Methods: Imaging mass cytometry for spatial immune profiling was performed on liver biopsy tissue. Flow cytometry was performed to dissect CD8 T-cell phenotypes and identify SARS-CoV-2-specific and EBV-specific T cells longitudinally. Vaccine-induced antibodies were determined by ELISA. Data were correlated with clinical laboratory results.

Results: Analysis of the hepatic tissue revealed an immune infiltrate quantitatively dominated by activated cytotoxic CD8 T cells with panlobular distribution. An enrichment of CD4 T cells, B cells, plasma cells and myeloid cells was also observed compared to controls. The intrahepatic infiltrate showed enrichment for CD8 T cells with SARS-CoV-2-specificity compared to the peripheral blood. Notably, hepatitis severity correlated longitudinally with an activated cytotoxic phenotype of peripheral SARS-CoV-2-specific, but not EBV-specific, CD8+ T cells or vaccine-induced immunoglobulins.

Conclusions: COVID-19 vaccination can elicit a distinct T cell-dominant immune-mediated hepatitis with a unique pathomechanism associated with vaccination-induced antigen-specific tissue-resident immunity requiring systemic immunosuppression.

Lay summary: Liver inflammation is observed during SARS-CoV-2 infection but can also occur in some individuals after vaccination and shares some typical features with autoimmune liver disease. In this report, we show that highly activated T cells accumulate and are evenly distributed in the different areas of the liver in a patient with liver inflammation following SARS-CoV-2 vaccination. Moreover, within the population of these liver-infiltrating T cells, we observed an enrichment of T cells that are reactive to SARS-CoV-2, suggesting that these vaccine-induced cells can contribute to liver inflammation in this context.

Keywords: Autoimmune hepatitis; CD8+ T cell; COVID-19; Immunosuppression; Vaccination; Virus-specific T cell.

Graphical abstract

Fig. 1

Clinical course with hepatitis after BNT162b2 vaccination. (A) Time course of ALT, AST, ALP, GGT and bilirubin levels after BNT162b2 vaccination in the patient. Arrows indicate the timepoint of BNT162b2 prime and boost vaccination. Arrowheads indicate timepoint of liver biopsy. Duration and dose of budesonide (9 mg/d) and prednisolone therapy (initially 50 mg/d) is shown in light blue and grey colorization. (B) Comparison of anti-spike S1 IgG antibody titers between patients and timepoint-matched vaccines who did not develop hepatitis. (C) Longitudinal analysis of anti-spike S1 IgG antibodies before and after the initiation of therapy. ALP, alanine phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; dpb, days post boost; GGT, gamma-glutamyltransferase.

Fig. 2

Deep spatial analysis of the hepatic immune environment reveals immune infiltration dominated by cytotoxic CD8 T cells. The liver biopsy was analyzed by highly multiplexed IMC. (A) Pseudocolored IMC images of the liver biopsy. Top left: Composite visualization of CD45, CK7, CD34, LYVE1, a-SMA and DNA are indicated by colors. Single marker visualization is shown for markers depicted on the left border of the visualizations. A region of interest is indicated by the box and detailed at higher resolution. Scale bars indicate 500 μm and 200 μm in the inserts, respectively. (B) Cell counts of immune cell subsets in the liver are shown as stacked barplots compared to controls. (C) Composite IMC image visualizing examples of liver zones defined by structural markers: Periportal (top), intermediate (middle) and centrilobular zones (bottom). Immune cell counts within the defined regions visualized as stacked barplots next to the respective inserts. Scale bars indicate 200 μm and 100 μm in the inserts, respectively. (D) Enrichment of indicated immune populations was calculated by dividing cell density in the patient sample by the mean of control samples. (E) Distribution of GrzB-positive CD8 T-cell and granulocyte cell counts within the liver zones. (F) Frequency (left) and cell density (right) of HLA-DR+ CD38+ CD8 T cells are shown for the patient with hepatitis and controls. GrzB, granzyme B; IMC, imaging mass cytometry.

Fig. 3

Immunophenotype of peripheral and vaccine-elicited CD8 T cells correlates with hepatitis severity. (A) t-SNE representation of flow cytometry data comparing non-naïve CD8+ T cells 27 dpb in the patient’s liver (red) and blood (blue). Expression levels of CXCR6, CD69, CD103 and CD38 are indicated (blue: low expression; red: high expression). (B) Quantified expression levels of CD38, 27 dpb on non-naïve CD8+ T cells within the patient’s liver (red) and blood (blue) compared to timepoint matched vaccinees without development of hepatitis. (C) Original bivariate plots showing frequencies of spike-specific (A∗03/S378) CD8+ T cells within the CD8+ T-cell population at 27 dpb, liver (red) and blood (blue). Expression levels of CXCR6, CD69, CD103 and CD38 of spike-specific CD8+ T cells are indicated. (D) Longitudinal analysis of calculated ex vivo spike-specific CD8+ T-cell frequencies. (E) Longitudinal analysis of CD38, (F) GrzB, (G) Tbet+CD38hi CD8+ T cells are shown with time-matched ALT (U/L) levels depicted in grey with connected dots, circulating non-naïve spike-specific CD8+ T cells (blue circle) and non-naïve bulk CD8+ T cells (grey open circle). Colored background indicates the patient’s therapy regime (light blue: budesonide, grey: prednisolone). ALT, alanine aminotransferase; dpb, days post boost; GrzB, granzyme B.