PD-1 AND ANTI-PD-1 ANTIBODIES DURING INFECTIONS OF THE CENTRAL NERVOUS SYSTEM

S. Stuard¹ and M. Rosati^2*

¹ Global Medical Office, FMC Germany, Bad Homburg, Germany;
² Department of Obstetrics and Gynecology, Spirito Santo Hospital, Pescara, Italy.

*Correspondence to:
Stefano Stuard, MD,
Global Medical Office,
FMC Germany,
Bad Homburg, Germany.
e-mail: Maurizio.rosati18@outlook.com

Received: 04 November, 2025 Accepted: 22 December, 2025

ISSN 2279-5855 print ISSN 2974-6345 online. Copyright © by BIOLIFE 2025 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

Programmed cell death type 1 (PD-1) is a receptor expressed on activated T lymphocytes that is capable of limiting excessive immune system activation. When PD-1 binds to its ligands PD-L1 and PD-L2, T lymphocyte inhibition occurs. Inhibition of the T cell receptor (TCR) reduces cell proliferation, cytokine production, inflammation, and cytotoxicity toward abnormal cells. PD-1 regulates the immune response in many pathological conditions, such as tumors, infections, autoimmune phenomena, and brain diseases. PD-1 plays an important role in diseases of the central nervous system (CNS) by regulating the immune response and preventing it from overreacting. PD-1 inhibits the excessive activation of microglia, preventing inflammatory processes. In many diseases, including brain tumors, anti-PD-1 monoclonal antibodies block the PD-1 signal and restore inhibition of CD8+ cells that act against tumor cells. However, the use of these antibodies must be done with caution, as they can cause immunosuppression and trigger diseases where T cells play a crucial role.

KEYWORDS: PD-1, anti-PD-1, antibody, infection, central nervous system, T cell

INTRODUCTION

Programmed cell death-1 (PD-1) (gene PDCD1) is an inhibitory receptor expressed on activated T cells capable of limiting excessive immune system activation, which is important in autoimmune diseases and inflammation (1).  PD-1 binds to its ligands PD-L1 and PD-L2 and prevents cellular and tissue damage caused by hyperactivated T-cell immunity (2).

PD-1 inhibits Toll-like receptors (TLRs), the receptors that recognize the pathogen, initiate the immune response, and prepare the environment for T-cell activation (3). The T cell receptor (TCR) initiates the activity of the cell and its inhibition by PD-1 reduces cell proliferation, cytokine production, and cytotoxicity (4). During infections, PD-1 is induced, which helps control pathogen-induced inflammation. The presence of microorganisms elevates PD-1 expression in T cells, while after elimination of the pathogen, PD-1 levels tend to decline and inflammation decreases (5). PD-1 prevents an excessive immune response, protecting tissues (6). If antigenic stimulation persists, PD-1 levels remain elevated.

DISCUSSION               

When T cells become incapable of functioning, the production of cytokines, such as interferon-gamma (IFN-γ), interleukin (IL)-2, and tumor necrosis factor (TNF), and the cytotoxic capacity toward foreign antigens decrease, resulting in a less effective immune system (7).  Pathogens then gain the upper hand, and the infection becomes chronic (2). Anti-PD-1 antibodies block the PD-1/PD-L1 interaction and thus reactivate T cells and the production of cytokines that mediate the immune response (8).

Inhibiting PD-1 can lead to chronic inflammation (hyperinflammation), triggering a cytokine storm with organ and tissue damage (9) (Fig.1). Anti-PD-1 antibodies reactivate T cells, thereby enhancing the immune response against infections. However, inhibition can lead to an exaggerated inflammatory reaction, resulting in tissue damage and dysregulation of the immune response.

Fig. 1. PD-1 is a T-cell immune checkpoint receptor when it binds to its ligands PD-L1 or PD-L2. Inhibition occurs primarily on TH1, TH2, and TH17 cells, resulting in inhibition of STAT3, STAT1/4, and STAT6.

When T cells experience functional exhaustion after chronic antigenic stimulation, they express inhibitory immune checkpoints such as PD-1, T-cell immunoglobulin mucin-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) (10). These inhibitory reactions, which act as an immune brake, can occur primarily in chronic infections and tumors (11).  In early T cell exhaustion, PD-1 is elevated, while in intermediate exhaustion, PD-1 + TIM-3 or TIGIT, and in terminal exhaustion, PD-1 + TIM-3 + LAG-3 + TIGIT, the levels are higher (12). These co-expressed molecules can synergistically increase immune inhibition, and blocking just one of these molecules is not sufficient to inhibit their effect.

Co-expression synergistically increases inhibition, and blocking a single checkpoint is not always sufficient to achieve a physiological effect. PD-1 transmits the PD-L1/PD-L2 signal, inhibits phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), TCR signalling, and cellular metabolism (13). TIM-3 binds galectin-9 and ICAM-1, inducing apoptosis or functional suppression of T cells (14) (Fig.2). LAG-3 binds MHC-II, reducing TCR signalling. TIGIT binds CD155 (DNAM-1), a potent inhibitor of natural killer (NK) cells and CD8^⁺ T cells (15).

Fig. 2. The PD-1 receptor binds to the ligands PD-1 and PD-L2 to exert its immunosuppressive effect. This effect leads to potential tumor growth. If PD-1 is blocked by a monoclonal antibody, it cannot bind to the ligands PD-L1 and PD-L2, restoring the immune effect by killing the tumor cell.

PD-1 and the central nervous system

PD-1 plays an important role in infections of the central nervous system (CNS), which activate T cells and generate inflammation (16).

PD-1 is an inhibitory receptor expressed primarily on CD4⁺ and CD8⁺ T cells, NK cells, and B cells (17). Endothelial cells, myeloid cells, astrocytes, and microglia express the ligand PD-L1 (CD274), while PD-L2 (CD273) is expressed primarily by dendritic cells and macrophages (18). PD-1 intervenes in the innate immune response by reducing TCR through phosphorylation, inhibits the generation of IFN-γ, TNF, and IL-2, and limits the proliferation of cytotoxic T cells, an important effect in limiting immune damage in autoimmune diseases (19).

PD-1 also plays a role in viral, bacterial, and parasitic cerebral infections. PD-1 is upregulated in T cells infiltrating the CNS, where it is expressed by activated microglia, endothelial cells comprising the blood-brain barrier (BBB), and astrocytes (20). PD-1 is a protective brake that can prevent certain brain diseases such as immune-mediated encephalitis by protecting neurons and synapses (21). It acts by limiting pathogen clearance and maintaining immune balance in the CNS. Inhibition of PD-1 leads to BBB permeability with increased infiltration of cytotoxic CD8^⁺ cells, IFN-γ, TNF, and granzymes, and neuronal damage with demyelization. Activation of PD-1 leads to control of effector T cells, reduced neurotoxicity, and persistence of the pathogen (22).

In CNS infections, anti-PD-1 antibodies such as nivolumab and pembrolizumab block the inhibitory signal, demonstrating that PD-1 is an effective biological brake (23).

PD-1 affects the reactivation of dysfunctional T cells, enhances the proliferation of cytotoxic CD8⁺ cells, and increases the production of pro-inflammatory cytokines. However, in experimental models, the major risks associated with PD-1 treatment are fulminant encephalitis, cerebral edema, and worsening clinical status (24).  Furthermore, PD-1 blockade increases mortality due to systemic pathological damage, amplifies T cell–microglia crosstalk, and promotes an M1-type inflammatory state linked to microglial activation (25). In these cases, pro-inflammatory cytokines, nitrous oxide (NO), and reactive oxygen species (ROS) are increased, with damage to neuronal survival, synapses, and myelin (26).  Therefore, PD-1 in the CNS is not only a negative checkpoint but is also an important regulator of the neuroimmune system, protecting brain tissue from immune damage by limiting the abnormal effect of T cells. PD-1 inhibition can be beneficial in autoimmune diseases, but also harmful if the immune system is blocked and rendered unresponsive to pathogens.

CONCLUSIONS

Anti-PD-1 drugs are monoclonal antibodies, such as pembrolizumab and nivolumab, that inhibit the PD-1 receptor. These antibodies bind to PD-1, preventing its reaction with its ligands L1 and L2 and reactivating T cell function. This reaction restores the T cell’s immune response, especially against tumors. Anti-PD-1 monoclonal antibodies are new pharmacological agents used in cancer immunotherapy where T cell reactivation is important. Conversely, the use of PD-1 may be useful in suppressing the T cell immune response in autoimmune diseases where T cells overrespond. PD-1 and its antibody, anti-PD-1, are crucial not only in oncology but also in the study of the CNS.

PD-1 regulates the brain’s immune system, preventing autoimmune hyperreaction, protecting brain tissue and neurons, and reducing inflammation. Anti-PD-1 monoclonal antibodies are useful for fighting tumors and brain metastases, where PD-1 inhibits the immune response. For example, melanoma and non-small-cell lung cancer are implicated in brain metastases. Although they do not cross the BBB, these drugs activate peripheral T cells, which then migrate into brain tissue. However, the use of these antibodies can excessively reactivate T cells, resulting in autoimmune reactions.

Conflict of interest

The authors declare that they have no conflict of interest.

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