PD-1 IS A KEY MOLECULE IN REGULATING THE IMMUNE RESPONSE DURING VIRAL INFECTIONS

Conti P, Langway J. PD-1 is a key molecule in regulating the immune response during viral infections. International Journal of Infection. 2026;10(2):27-28.

P. Conti^1* and J. Langway²

¹ Immunology Division, Postgraduate Medical School, University of Chieti, Chieti, Italy;
² Tufts University, Boston, USA.

*Correspondence to:
Prof. Pio Conti,
Immunology Division,
Postgraduate Medical School,
University of Chieti,
66100 Chieti, Italy.
e-mail: pioconti@yahoo.it

Received: 28 April, 2026 Accepted: 29 May, 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.

KEYWORDS: PD-1, receptor, viral infection, immune response, inhibitory

INTRODUCTION

Viral infections interact with the host immune response. The virus binds to specific pattern recognition receptors (PRRs) (Toll-like receptors (TLRs) or RIG-I-like receptors) located on the cell surface, enters the cell, and releases its genome, which can be RNA or DNA (1). Viruses use ribosomes and enzymes to replicate and produce viral proteins that interact with cellular machinery (2).

Viral receptors recognize pattern associated molecular patterns (PAMPs), as occurs with viral RNA, and activate intracellular signalling via NF-κB and IRF3, leading to the production of interferon (IFN)-α, IFN-β, and inflammatory cytokines (3). Excessive immune responses are physiologically limited by the expression of inhibitory receptors on immune cells. Chronic viral infections result in persistent antigenic stimulation, which in turn, causes immune dysfunction. T cells activated via the T-cell receptor (TCR) increase the expression of several inhibitory checkpoint receptors, such as CTLA-4, TIGIT, TIM-3, LAG-3, and Programmed Death-1 (PD-1).

PD-1 is an inhibitory receptor expressed primarily on activated T cells, B cells, and natural killer (NK) cells (4). In acute viral infections, transient expression occurs, leading to fine-tuning of the response, while in chronic infections, expression is persistent and causes T cell exhaustion. Viruses can cause molecular effects that include the recruitment of phosphatases such as SHP-1 and SHP-2 and the inhibition of TCR signalling via PI3K-Akt, resulting in reduced cell proliferation, cytokine production, and cytotoxicity. In chronic infection, the coexpression of PD-1, TIM-3, and LAG-3 leads to a state of severe dysfunction. The expression of inhibitory receptors such as BTLA, FcγRIIB, CD22, and PD-1 (in some subpopulations) also occurs on B cells, especially after activation. These receptors regulate B cell receptor (BCR) signalling on B lymphocytes and limit antibody production, activation, and differentiation.

NK cells are controlled by a balance between activating and inhibitory signals. The main inhibitory receptors are NKG2A, killer immunoglobulin-like receptors (KIR), TIGIT, and PD-1 in pathological conditions (5). NK cell signalling involves recognition of major histocompatibility complex (MHC) class I, which induces an inhibitory signal and activates the phosphatases SHP-1 and 2. This leads to the blockade of degranulation, IFN-γ production, and cytotoxicity. In chronic viral infections, NKG2A and PD-1 are increased, resulting in reduced cytotoxicity. Risks that may arise include functional exhaustion of T, B, and NK cells with viral persistence.

DISCUSSION        

PD-1 is an inhibitory receptor expressed primarily on activated T lymphocytes, B lymphocytes, and NK cells. The main ligands of PD-1 are PD-L1 (B7-H1) and PD-L2 (B7-DC), which can be expressed by both antigen-presenting cells and virally infected cells. The molecular mechanism by which these reactions occur begins with signalling activation when PD-1 binds to its ligands PD-L1 or PD-L2, which differ in expression, regulation, and functional role in controlling the immune response (6). These ligands bind to the PD-1 receptor on T lymphocytes and transmit inhibitory signals, reducing T lymphocyte proliferation, cytokine production, and cytotoxic activity. Therefore, PD-L1 acts as a broad-spectrum brake on the immune system, while PD-L2 is a more selective and regulated brake.

PD-L1 is expressed by dendritic cells and macrophages, non-immune cells such as epithelial and endothelial cells, and many tumors; while PD-L2 is expressed primarily on dendritic cells and macrophages. PD-L1 is induced by IFN-γ and inflammation, while PD-L2 is regulated by the cytokines IL-4 and IL-13. The ligand-receptor reaction leads to the recruitment of the phosphatase SHP-2 and associates with the intracellular motifs of PD-1 (ITIM and ITSM) (7). SHP-2 dephosphorylates the key molecules CD3ζ, ZAP-70, and PI3K of the TCR cascade, resulting in inhibition of the cascade itself. This leads to a decrease in several parameters such as activation of the PI3K-Akt pathway, T-cell proliferation, IL-2 production, and cell survival. Furthermore, PD-1-mediated signalling leads to reduced production of cytokines such as IFN-γ, TNF, and IL-1, reduced cytotoxicity, and functional anergy of T lymphocytes.

In acute viral infections, such as those of the lower respiratory tract (e.g., pneumonia, acute bronchitis, bronchiolitis, and influenza), PD-1 is transiently activated and serves to limit pathological immune damage and restore the T cell response after virus clearance. In chronic infections, such as HIV infection or hepatitis C, amongst others, persistent PD-1 expression on T lymphocytes leads to T cell exhaustion. In these cases, the inability to clear the virus results in a progressive loss of function and the maintenance of viremia.

CONCLUSIONS

In conclusion, PD-1 is an “immune brake” system that protects against excessive tissue damage, promotes viral persistence if overactive, and has therapeutic implications. Blocking PD-1/PD-L1 can reactivate exhausted T lymphocytes and is already used in oncology as an immune checkpoint inhibitor and is also being studied in chronic viral infections.

Conflict of interest

The authors declare that they have no conflict of interest.

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