ROLE OF Tregs IN HERPES SIMPLEX ENCEPHALITIS

Carusi V, Paolucci T. Role of Tregs in Herpes simplex encephalitis.  International Journal of Infection. 2026;10(2):46-49.

V. Carusi^1* and T. Paolucci²

¹ Allergy and Clinical immunology, Policlinico Gemelli, Rome, Italy;
² Department of Oral, Medical and Biotechnological Sciences, University of Study “G. d’Annunzio” of Chieti, Italy.

*Correspondence to:
Dr. Valentina Carusi,
Allergy and Clinical immunology,
Policlinico Gemelli,
Rome, Italy.
e-mail: valentina.carusi1@guest.policlinicogemelli.it

Received: 02 June, 2026 Accepted: 13 July, 2026

ISSN 3103-6678 [online] Copyright 2026 © by Biolife Publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis by suppressing excessive inflammatory and autoimmune responses, limiting tissue damage, and promoting repair within the central nervous system (CNS). Tregs help reduce neuroinflammation and support neuronal recovery during infections of the brain and in neurological disorders, although excessive immunosuppression may impair pathogen clearance and contribute to persistent or chronic infection. Herpes simplex virus (HSV)-1 and -2 establishes lifelong latency after primary infection and can reactivate to invade the CNS, where it infects neurons through retrograde axonal transport and causes herpes simplex encephalitis (HSE). Viral replication induces neuronal death and brain tissue necrosis, while the resulting immune response activates microglia, astrocytes, and T cells, including Tregs, which help limit inflammation, viral activation, and neurological damage. HSV-1 and HSV-2 are closely related double-stranded DNA viruses of the Herpesviridae family that share most of their genome and cellular entry receptors but differ in key glycoproteins, regulatory proteins, and patterns of latency and reactivation, with HSV-1 primarily affecting the trigeminal ganglia and HSV-2 the sacral ganglia. HSV-1 can spread from the oral mucosa to the CNS via sensory neurons, where viral replication triggers neuronal death, immune cell activation, inflammation, and, in severe cases, HSE.

KEYWORDS: Regulatory T cell, Treg, Herpes simplex virus, encephalitis, CNS, neuroinflammation

INTRODUCTION

Herpes simplex virus (HSV) can cause a common viral infection, and potentially, the life-threatening condition herpes simplex encephalitis (HSE) (1). HSV is transmitted through direct contact with lesions, infected secretions, saliva, and sexual intercourse (2). After the initial infection, HSV remains latent in the body and can reactivate after a period of time; reactivation can be caused by other infections, stress, immunosuppression, ultraviolet light exposure, and trauma (3). HSV can cause painful blisters consisting of small fluid-filled vesicles clustered on inflamed tissue (4). When the blisters rupture, they cause burning, itching, and tingling, leaving small ulcers that later form a crust, which generally heal after about seven to ten days without scarring.

HSE is a serious, potentially life-threatening neurological condition where brain tissue becomes inflamed and damaged. This viral encephalitis is caused by herpes simplex virus-1 (HSV-1) in approximately 90% of cases, with the other 10% resulting from herpes simplex virus-2 (HSV-2), both of which are common viral infections that are usually spread within the population through skin-to-skin contact. However, HSE is rare, and can occur when the virus spreads to the brain through a nerve.

Lymphocytes are immune cells responsible for defending the body from foreign pathogens, such as viruses, bacteria, and fungi, and for recognizing and destroying abnormal or tumor cells (5). T lymphocytes act directly against infections and coordinate the entire immune response (5,6). Regulatory lymphocytes perform an immunosuppressive function and inhibit the activation of immune responses against the body’s own self-cells (7,8). Regulatory T cells (Tregs) are responsible for limiting inflammation, preventing excessive autoimmune responses, and promoting tissue repair (7-9). In the central nervous system (CNS), Tregs are the subject of intense research because they appear to influence several neurological diseases (9-11).

Tregs play an important role in autoimmune and inflammatory neuropathies, helping to control the immune response (10,12). In Parkinson’s disease, increased Treg activity can reduce neuroinflammation and protect neurons (13,14). In Alzheimer’s disease, Tregs help modulate neuroinflammation (15,16), while in stroke, they appear to help reduce inflammatory damage and promote the healing process (17,18).

Tregs also play a crucial role in brain infections, where they must strike a balance between containing inflammation and not hindering the elimination of the pathogen (19,20). Infection in the CNS activates the immune system, where Tregs participate in limiting the damage to neurons caused by excessive inflammation and reduce the production of pro-inflammatory cytokines (19,20). Additionally, Tregs can promote the repair of nervous tissue once the infection has subsided (9,20). However, Tregs can also be harmful by suppressing the immune response necessary to eliminate the pathogenic virus, thus promoting the persistence or chronicity of the infection (19,20).

HERPES SIMPLEX ENCEPHALITIS

HSV can invade the CNS and cause an intense inflammatory response that can result in HSE, a severe neurological emergency (21). The virus infects epithelial cells of the oral mucosa and subsequently enters neurons (22). It infects sensory nerve endings and ascends the axons via retrograde axonal transport to the sensory ganglia, particularly the trigeminal ganglion (23). HSV can remain latent in sensory ganglia and, in rare cases, spread to the brain, where reactivation most commonly affects the medial temporal lobes and inferior frontal lobes (24). In the brain, the virus binds to cellular receptors such as nectin-1 and herpesvirus entry mediator (HVEM), enters neurons by membrane fusion, and uses the host-cell machinery to transcribe and replicate its DNA (25).

Viral replication leads to the synthesis of new particles that infect nearby cells, causing neuronal lysis, apoptosis, and brain tissue necrosis (26). Infection triggers an immune response that activates microglia and astrocytes, which contribute to inflammation and infiltration by T cells, including Tregs, which limit viral activation, inflammation, and brain damage (27).

HSV-1 and HSV-2 viruses exhibit some genetic and molecular differences (Table I). They are linear double-stranded DNA viruses belonging to the Herpesviridae family (28). HSV-1 has a genome of approximately 152 Kb, while HSV-2 is approximately 154 Kb, and they share around 83% nucleotide sequence identity. The genetic differences between the two viruses are primarily located in the genes encoding glycoprotein G (gG) (29). In fact, gG-1 and gG-2 are antigenically different. gC, gE, gI, and gD have different sequences and are capable of influencing cell adhesion, immune evasion, and viral spread. The viral regulatory proteins ICP34.5 and ICP0 counteract the immune response differently and regulate viral replication (30). HSV-1 and HSV-2 use the same receptors: Nectin-1, HVEM, and heparan sulfate. However, HSV-1 reactivates more frequently in the trigeminal ganglia, while HSV-2 tends to establish latency in the sacral ganglia, more often causing genital herpes (1,22).

Table I. Characteristics of Herpes simplex virus (HSV)-1 and -2.

HSV-1 can infect the oral mucosa and initially involve the trigeminal ganglion, which activates the CNS and leads to infection of neurons. The virus then replicates its DNA, causing neuronal lysis and apoptosis, microglia and lymphocyte activation, inflammation, and encephalitis (31).

CONCLUSIONS

Tregs play a dual role in HSE by limiting excessive neuroinflammation and promoting tissue repair while potentially reducing the immune response required for complete viral clearance. A better understanding of the interactions between HSV infection, host immune responses, and Treg function may provide new therapeutic strategies that balance antiviral immunity with neuroprotection, improving outcomes for patients with HSE. Strategies for manipulating regulatory lymphocytes for therapeutic purposes could be useful not only for the treatment of autoimmune and allergic diseases, but also for various types of cancer, and viral infections.

Conflict of interest

The authors declare that they have no conflict of interest.

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