In many pediatric acute liver failure (PALF) instances, no diagnosis is made, and the cause is unknown (IND-PALF). In the livers of IND-PALF patients, researchers discovered extensive CD8 T-cell infiltrates and enhanced T-cell clonality. They wanted to confirm these findings in a multicenter cohort with investigators who were not aware of the diagnosis. Subjects from the PALF Study Group registry with IND-PALF and known diagnoses, ages 1 to 17 years, and archived liver tissue were included. T cells (CD8 and CD4), B cells (CD20), macrophages (CD163), perforin, and tissue resident-memory T cells were stained on liver tissue slides and graded as minimum, moderate, or dense. T-cell receptor beta (TCR) sequencing was performed on lymphocytes obtained from frozen liver tissue. Significantly more IND-PALF individuals had dense hepatic CD8 staining than DX-PALF subjects. When compared to DX-PALF individuals, IND-PALF subjects were more likely to exhibit dense or moderate perforin and CD103 staining. TCR sequencing of 15 IND-PALF patients revealed more clonal overlap than 6 DX-PALF cases.

The liver tissue of IND-PALF patients has a dense infiltration of effector Trm CD8 T cells. Increased clonality implies that T-cell proliferation is driven by antigen(s) rather than a generic inflammatory response. These results support the use of CD8 staining as a novel biomarker of the activated CD8 T-cell PALF phenotype. Future research is required to define possible antigens, host risk factors, and inflammatory pathways in order to create targeted treatments.