There are currently no animal models of drug-induced liver injury (DILI) where the adaptive immune system has been shown to damage the liver. Thus, it is difficult to explore the mechanistic basis of the tissue injury. The aim of this study was to use C57BL/6 CD4+-deficient mice with a mutation in the αβ gene encoding for Major histocompatibilty complex (MHC) class II molecules to (1) develop a mouse model of flucloxacillin sensitization, (2) explore whether drug-specific CD8+ kill primary hepatocytes, and (3) analyze perturbations in liver integrity following oral exposure to flucloxacillin. CD8+ T-cells from lymph nodes of flucloxacillin-sensitized mice were stimulated to proliferate, secrete interferon (IFN-γ) and granzyme B, and induce hepatocyte apoptosis in a concentration-dependent manner following ex vivo stimulation. The T-cell response was antigen-specific; T-cells were not activated with other β-lactam antibiotics. Furthermore, T-cell responses only occurred in the presence of flucloxacillin-pulsed antigen presenting cells. In separate experiments, flucloxacillin-specific T-cells were induced to migrate to the mesenteric lymph nodes using retinoic acid, prior to administration of oral flucloxacillin, and analysis of plasma biomarkers of liver injury. Oral exposure to flucloxacillin resulted in mild elevations in alanine aminotransferase, liver, and gall bladder leukocyte infiltration and a marked swelling of the gall bladder. Thus, CD4+-deficient mice represent a promising model to study the role of the adaptive immune system in DILI.

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Age is associated with changes in the immune system which increase the risk for severe COVID‐19. Here, we investigate SARS‐CoV‐2‐reactive CD4 T cells from individuals recovered from SARS‐CoV‐2 infection with mild COVID‐19 symptoms after 3, 6 and 9 months using incubation with SARS‐CoV‐2 S1, S2 and N‐peptide pools, followed by flow cytometry for a Th1‐activation profile or proliferation analyses. We found that SARS‐CoV‐2‐reactive CD4 T cells are decreasing on average after 9 months but highly polyfunctional CD4 T cells can peak after 6‐month recovery. We show that individuals older than 60 years of age have significantly more SARS‐CoV‐2‐reactive T cells in their blood after 3 months of recovery compared to younger individuals and that the percentage of SARS‐CoV‐2‐reactive Th1‐directed CD4 T cells in the blood of mild‐COVID‐19‐recovered individuals correlates with age. Finally, we show that individuals over the age of 40 have significantly increased the amounts of highly polyfunctional SARS‐CoV‐2‐S‐peptide‐reactive CD4 T cells, compared to SARS‐CoV‐2 naïve individuals, than those under the age of 40. These findings suggest that in individuals recovered from mild COVID‐19, increased age is associated with significantly more highly polyfunctional SARS‐CoV‐2‐reactive CD4 T cells with a Th1‐profile and that these responses persist over time.

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