CD8 T cell dynamics and immune cell trafficking in ZIKV infection: implications for neuroinflammation and therapy

Abstract

The 2015-2016 Zika virus (ZIKV) epidemic underscored the severe consequences of congenital Zika syndrome (CZS) and the broader challenges posed by neurotropic flaviviruses. As key mediators of cytotoxic immunity, CD8 T cells play a crucial and multifaceted role in ZIKV pathogenesis. While essential for controlling viral replication, their infiltration into the central nervous system (CNS)-an immune-privileged site-raises potential concerns regarding immunopathology. This review explores the dual roles of CD8 T cells during ZIKV infection, emphasizing both their antiviral functions and their potential to drive neuroinflammation. We examine how ZIKV infection and chemokine-mediated signals facilitate immune cell trafficking across the blood-brain barrier, drawing parallels with other neurotropic flaviviruses. We also explore how therapeutic agents, such as the S1P receptor modulator FTY720, influence lymphocyte trafficking and CNS immune regulation. Finally, we review emerging interventions-including vaccines, antivirals, immunomodulators, and passive immunotherapies-that aim to achieve effective viral control while minimizing neural damage. A balanced understanding of immune cell responses in flavivirus infections is essential for guiding future therapeutic strategies against ZIKV and related neurotropic viruses.

Keywords: CD8 T cells; Central nervous system; FTY720; Flaviviruses; Immune cells infiltration; Neuroinflammation; Zika virus.

Fig. 1

CD8 T cells are central effectors of antiviral adaptive immunity. CD8 T cells are key players in antiviral defense. Upon activation by viral peptides presented on MHC class I molecules, naïve CD8 T cells differentiate into effector cells that eliminate infected cells via perforin–granzyme, FasL–Fas, and TRAIL–DR5 apoptotic pathways. They also secrete cytokines (e.g., IFN-γ, TNF-α, IL-2) and chemokines (e.g., CCL3/4/5) that amplify immune responses and inhibit viral replication. A subset of these cells persists as memory CD8 T cells—including TCM, TEM, and TRM—providing long-term protection and rapid recall responses upon reinfection

Fig. 2

Chemokine-mediated infiltration of peripheral immune cells into the CNS during flavivirus infection. The CNS, typically an immune-privileged site, becomes accessible to peripheral immune cells during flavivirus infection through a combination of BBB disruption and chemokine-driven recruitment. Flavivirus-infected monocytes expressing CCR2 and CCR5 may cross the BBB via a “Trojan horse” mechanism, carrying viral particles into the CNS. Within the CNS, astrocytes and microglia respond to infection by producing chemokines such as CCL2 and CXCL1, which recruit monocytes and neutrophils via CCR2 and CXCR2, respectively. CD8 T cells are attracted by CXCL10 secreted by infected neurons, engaging CXCR3. A subset of CCR2-expressing CD8 T cells persists as TRM cells and exerts neuroprotective functions. Endothelial cells contribute to immune cell entry by expressing adhesion molecules and secreting CCL5, which binds to CCR5. While CD8 T cells are essential for controlling viral spread, their accumulation in the CNS may also cause collateral neuronal damage and contribute to flavivirus-associated neuropathology

Fig. 3

Mechanism of FTY720 (fingolimod) in regulating lymphocyte trafficking via S1P₁ receptor modulation. Under normal physiological conditions, lymphocytes in secondary lymphoid organs (SLOs) express the S1P₁, which senses the S1P gradient between the SLO (low S1P) and lymph/blood (high S1P). This gradient allows activated lymphocytes to exit the SLO and migrate into circulation, facilitating tissue infiltration. When FTY720 is phosphorylated into its active form (FTY720-P), it binds to S1P₁ on lymphocytes, triggering receptor internalization and degradation. This downregulates surface S1P₁ expression and impairs the lymphocytes’ ability to respond to the S1P gradient. As a result, lymphocyte egress is blocked, leading to their sequestration within SLOs and reduced migration to peripheral tissues, including inflamed sites such as the CNS