The nature and pathogenesis of liver diseases associated with t follicular regulatory and T follicular helper cell subsets: A narrative review.

Abstract

The immune system relies on a delicate equilibrium between activation and suppression to sustain homeostasis, and the disruption of this balance is a central feature in the pathophysiology of liver diseases. Among the key regulators of this process are T follicular helper (TFH) and T follicular regulatory (TFR) cells, which orchestrate B cell responses through reciprocal functions. TFH cells promote B cell differentiation, antibody production, and memory formation, whereas TFR cells suppress TFH and B cell activity, collectively acting as guardians of immune balance. The liver, which is the body's main organ for filtering blood, is especially vulnerable to pathogen- and damage-associated molecular patterns. Excessive immune activation in this context can drive hepatocyte injury, inflammation, fibrosis, and ultimately immune exhaustion. Alterations in the number and functionality of TFH and TFR cells, alongside their associated cytokine milieu, have been increasingly recognized across diverse liver diseases and with their pathogenesis. Different etiologies of liver disease, ranging from viral hepatitis and alcohol-related injury to autoimmune and genetic causes, present with distinct clinical and pathological features. Yet, a common thread is the dysregulated immune profile, where deviations in TFH and TFR dynamics represent both convergent and disease-specific patterns. A deeper understanding of their functional roles across different disease states offers predictive insight into liver-associated immune complications. This narrative review highlights a current understanding of TFH and TFR cells in liver disease, emphasizing their impact on progression, value as biomarkers, and therapeutic potential, while outlining how their regulatory balance informs disease mechanisms and treatment approaches.