PDCD1LG2 - programmed cell death 1 ligand 2 | Elisa - Clia - Antibody - Protein

Background

Programmed cell death 1 ligand 2 (PDCD1LG2), commonly referred to as PD-L2, is an immune regulatory protein that belongs to the B7 family of immune checkpoint ligands. PD-L2 functions as a ligand for PD-1 (Programmed Cell Death Protein 1), an inhibitory receptor on T cells, and contributes to the modulation of immune responses by promoting T cell inhibition. This ligand is highly relevant in immune tolerance, particularly in peripheral tissues where it helps prevent excessive immune reactions that could lead to tissue damage. PD-L2, together with its better-known counterpart PD-L1, plays a key role in immune escape mechanisms in cancers, where it inhibits T cell activation and proliferation, enabling tumor cells to evade immune surveillance.

PD-L2 is selectively expressed on antigen-presenting cells (APCs) such as dendritic cells (DCs), macrophages, and B cells. Its expression is inducible, being upregulated under conditions of inflammation or during immune activation through signals like interleukin-4 (IL-4) and interferon-gamma (IFN-γ). This selective and inducible expression of PD-L2 suggests it has specialized roles in fine-tuning immune responses, distinguishing it from PD-L1, which is more broadly expressed across various cell types, including non-immune cells.

Protein Structure

PD-L2 is a type I transmembrane glycoprotein composed of 273 amino acids, with a structure characteristic of the B7 family of immune checkpoint ligands. It consists of three main domains: an extracellular region, a transmembrane domain, and an intracellular tail. Each domain has a specific role in facilitating PD-L2’s function as an immune modulator:

Extracellular Domain:

• The extracellular region of PD-L2 contains two immunoglobulin (Ig) domains: a distal IgV-like domain and a proximal IgC-like domain. These domains contribute to PD-L2's ability to bind to PD-1 with high affinity.
• The IgV-like domain is responsible for the binding interface with PD-1. Structural studies indicate that PD-L2 binds more selectively and with a higher affinity to PD-1 compared to PD-L1. The binding site involves key amino acids in the IgV-like domain that interact with PD-1, stabilizing the receptor-ligand complex and transmitting inhibitory signals to PD-1-expressing cells.
• The IgC-like domain stabilizes the structure and orientation of the IgV-like domain, enabling PD-L2 to maintain a conformation favorable for PD-1 interaction.

Transmembrane Domain:

• The transmembrane domain of PD-L2 anchors it in the cell membrane, facilitating its stable expression on the surface of immune cells. This domain is important for PD-L2 localization and allows it to interact effectively with PD-1 on adjacent T cells.

Intracellular Domain:

• The intracellular domain of PD-L2 is relatively short and lacks classical signaling motifs, suggesting that PD-L2’s primary function is through interaction with PD-1 rather than initiating direct intracellular signaling.
• The lack of signaling motifs in the intracellular tail of PD-L2 further underscores its role as a ligand that modulates PD-1-mediated signaling rather than transmitting signals into the antigen-presenting cell itself.

Overall, the structure of PD-L2 supports its function as a highly specific ligand for PD-1, designed to inhibit immune responses through extracellular engagement with PD-1 rather than signaling within the APC.

Classification and Subtypes

PD-L2 is classified within the B7 family of immune checkpoint ligands, which are part of the larger immunoglobulin superfamily. This family includes molecules like PD-L1 (PDCD1LG1), B7-1 (CD80), B7-2 (CD86), and B7-H3 (CD276), among others, which modulate T cell responses and immune tolerance. PD-L2 is closely related to PD-L1 in terms of function, as both serve as ligands for PD-1. However, PD-L2 and PD-L1 differ in their expression patterns, binding affinities, and specific immunological contexts in which they are upregulated, giving each a unique role in immune regulation.

PD-L2 does not have identified subtypes or isoforms. Its structural and functional specificity is attributed to its binding to PD-1 and is consistent across its expression on various APCs.

Function and Biological Significance

PD-L2 plays a critical role in the regulation of immune responses, particularly in maintaining peripheral tolerance, modulating T cell activity, and preventing autoimmune reactions. Key functions and biological significance of PD-L2 include:

Inhibition of T Cell Activation:

• By binding to PD-1, PD-L2 delivers an inhibitory signal that reduces T cell activation, proliferation, and cytokine production. This inhibition is essential in preventing overactivation of T cells, which can lead to excessive inflammation and tissue damage.
• PD-L2 is typically expressed on professional antigen-presenting cells, such as dendritic cells and macrophages, particularly in inflamed tissues. Through PD-1 engagement, PD-L2 helps suppress effector T cells at sites of inflammation, maintaining immune homeostasis and reducing the risk of tissue injury.

Regulation of Immune Tolerance:

• PD-L2 is upregulated in conditions where immune tolerance is required, such as in response to anti-inflammatory cytokines (e.g., IL-4). This mechanism is particularly important in tissues exposed to environmental antigens, such as the lungs and gut, where continuous immune surveillance is necessary without overactivation.
• By inhibiting T cell activation through PD-1 engagement, PD-L2 prevents immune reactions against self-antigens and promotes tolerance to non-harmful environmental antigens.

Role in Cancer Immunity:

• PD-L2 is expressed on tumor-associated macrophages and other cells within the tumor microenvironment, where it contributes to immune evasion. Cancer cells and surrounding stroma can exploit PD-L2’s inhibitory effects on T cells, reducing the effectiveness of anti-tumor immunity and enabling tumor growth and metastasis.
• PD-L2 expression has been observed in various cancers, including lung cancer, esophageal cancer, and melanoma. Tumors expressing high levels of PD-L2 can evade immune detection, making PD-L2 a target of interest in cancer immunotherapy.

Pathogen Immune Evasion:

• Some pathogens, such as certain viruses and bacteria, induce PD-L2 expression on APCs to evade immune responses. By promoting PD-L2 expression, these pathogens exploit PD-L2's inhibitory effects on T cells, allowing them to persist within the host by blunting adaptive immune responses.
• This mechanism has implications for chronic infections, where sustained PD-L2 expression can hinder effective immune clearance, facilitating prolonged pathogen survival and chronic disease states.

Clinical Issues

PD-L2 has significant implications in clinical settings related to autoimmunity, cancer immunotherapy, and chronic infections:

Autoimmune Diseases:

• Dysregulation of PD-L2 expression or PD-1/PD-L2 interactions can contribute to autoimmune diseases. Reduced expression of PD-L2 or PD-1 signaling dysfunction can lead to excessive T cell activity and the development of autoimmune conditions like rheumatoid arthritis and type 1 diabetes.
• Therapeutic strategies aimed at enhancing PD-L2 function or PD-1 engagement could mitigate autoimmune responses, providing potential treatment options for autoimmune conditions characterized by unchecked immune activation.

Cancer Therapy:

• In cancer, PD-L2 is often upregulated within the tumor microenvironment, contributing to immune escape. PD-1/PD-L2 inhibitors have emerged as promising therapies in cancers with high PD-L2 expression, as blocking PD-L2 can reactivate T cells and restore anti-tumor immunity.
• Current PD-1/PD-L1 therapies, such as nivolumab and pembrolizumab, target the PD-1/PD-L1 axis but may also impact PD-1/PD-L2 interactions. Research is ongoing to develop therapies specifically targeting PD-L2 in cancers where it is a dominant immune evasion mechanism.

Chronic Infections:

• PD-L2 expression is often upregulated in chronic infections, contributing to pathogen persistence by suppressing T cell responses. Pathogens that exploit PD-L2-mediated inhibition of T cells can evade immune clearance and establish chronic infections.
• Therapeutic strategies that modulate PD-L2 levels or block its interaction with PD-1 could be beneficial in treating chronic infections by enhancing immune responses against the pathogen.

Summary

PD-L2 is an immune checkpoint ligand that plays a crucial role in regulating T cell responses and maintaining immune tolerance. Structurally, it consists of an extracellular domain with IgV and IgC regions, a transmembrane domain, and a short intracellular tail. PD-L2’s binding to PD-1 on T cells transmits an inhibitory signal that reduces T cell activation, cytokine production, and proliferation. This interaction is essential for maintaining immune homeostasis and preventing overactivation of T cells, which could lead to autoimmune reactions.

PD-L2 is expressed on antigen-presenting cells, where it is upregulated in response to inflammatory signals or during immune activation. Clinically, PD-L2’s function has implications in autoimmune disease prevention, cancer immunotherapy, and chronic infection management. PD-L2 expression in the tumor microenvironment allows tumors to evade immune detection by inhibiting T cell responses, making it a significant target for cancer immunotherapy. In autoimmune diseases, enhancing PD-L2 function could help restore tolerance and mitigate excessive immune activation. In chronic infections, reducing PD-L2-mediated inhibition could enhance pathogen clearance.

Given its critical role in immune modulation, PD-L2 represents an essential target for therapies designed to modulate immune responses in a variety of diseases, from cancer and autoimmunity to chronic infections.