# Lymphocyte function inhibition and exhaustion in sepsis: mechanisms and applications

## TL;DR

This review explores how lymphocyte dysfunction contributes to sepsis and highlights potential strategies for immune monitoring and treatment.

## Contribution

The paper systematically organizes mechanisms of lymphocyte inhibition in sepsis and discusses their clinical and therapeutic implications.

## Key findings

- Lymphocyte dysfunction in sepsis involves multiple interconnected pathways, including immune checkpoint receptors and metabolic dysregulation.
- Lymphocyte-based indicators show promise for early risk assessment and prognosis in sepsis.
- Targeting immune checkpoints and metabolic dysfunction offers potential therapeutic strategies for sepsis.

## Abstract

Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host response to infection and is characterized by complex pathophysiological mechanisms in which immune dysfunction plays a central role. Among immune cells, lymphocytes are critically involved in both the progression and resolution of sepsis. Increasing evidence indicates that lymphocyte depletion, functional exhaustion, and phenotypic reprogramming are closely associated with persistent immunosuppression and adverse clinical outcomes. This review examines the major mechanisms underlying lymphocyte function inhibition in sepsis and organizes them into interconnected pathways, including inhibitory membrane receptors (such as PD-1, CTLA-4, and LAG-3), mitochondrial and endoplasmic reticulum stress–related organelle dysfunction, exosome-mediated intercellular communication, non-coding RNA regulatory networks, and cytokine-driven immune modulation. These mechanisms interact through shared intracellular signaling pathways, contributing to impaired proliferation, altered cytokine production, metabolic dysregulation, and apoptosis of lymphocytes. The clinical relevance of lymphocyte-based indicators is also discussed, including absolute lymphocyte counts, subpopulation distribution, and immune checkpoint expression, which show potential value in early risk stratification and prognostic assessment. In addition, emerging therapeutic strategies targeting immune checkpoints and immunometabolic dysfunction are summarized. These insights provide a structured understanding of lymphocyte inhibition in sepsis and offer potential directions for improving immune monitoring and developing individualized immunomodulatory interventions.