Cytotoxic T lymphocytes and their dual role in modulating blood-brain barrier integrity in immune-mediated neurological pathologies

TL;DR

This paper explains how cytotoxic T cells can both protect and harm the blood-brain barrier in neurological diseases.

Contribution

The paper provides a unified framework of three mechanisms by which CTLs modulate BBB integrity in immune-mediated neurological disorders.

Findings

CTLs can damage the BBB through direct cytotoxicity, inducing endothelial cell apoptosis.

Proinflammatory cytokines like IFN-γ and TNF-α activate pathways that disrupt BBB integrity.

Chemokines such as CXCL10 and CCL5 promote immune cell migration across the BBB.

Abstract

The blood-brain barrier (BBB) is a dynamic, multicellular interface that preserves central nervous system (CNS) homeostasis by restricting entry of pathogens and circulating cells. Cytotoxic T lymphocytes (CTLs), comprising both CD8⁺ and CD4⁺ subsets, are central to adaptive immunity through targeted elimination of infected or transformed cells. However, in immune-mediated neurological disorders, including viral encephalitis, multiple sclerosis, Parkinson’s disease, and glioma, CTLs effector functions can inadvertently compromise BBB integrity. Here, we integrate findings from primary research to delineate three principal mechanisms by which CTLs modulate the BBB: (1) direct cytotoxicity, in which perforin/granzyme release and FasL-Fas interactions induce endothelial cell apoptosis; (2) proinflammatory cytokine signaling, notably IFN‑γ and TNF‑α activation of JAK/STAT and NF‑κB pathways in brain microvascular endothelial cells; and (3) chemokine‑driven leukocyte trafficking, wherein CXCL10 and CCL5 gradients promote CTLs and bystander immune cell migration across the barrier. We further review evidence from in vitro and in vivo models that illustrate both protective and deleterious roles of CTLs at the neurovascular interface. By clearly specifying these mechanisms and their disease‑specific contexts, this review establishes a unified framework for future investigations aimed at preserving BBB function while maintaining effective CTL‑mediated immunity.

The online version contains supplementary material available at 10.1186/s12967-025-07288-3.

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