PD-L2

Official Full Name

programmed cell death 1 ligand 2

Organism

Homo sapiens

GeneID

80380

Background

Involved in negative regulation of activated T cell proliferation; negative regulation of interleukin-10 production; and negative regulation of type II interferon production. Predicted to be located in plasma membrane. Predicted to be active in external side of plasma membrane. Biomarker of pulmonary tuberculosis. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

B7DC; Btdc; PDL2; CD273; PD-L2; PDCD1L2; bA574F11.2;

Bio Chemical Class

Immunoglobulin

Protein Sequence

MIFLLLMLSLELQLHQIAALFTVTVPKELYIIEHGSNVTLECNFDTGSHVNLGAITASLQKVENDTSPHRERATLLEEQLPLGKASFHIPQVQVRDEGQYQCIIIYGVAWDYKYLTLKVKASYRKINTHILKVPETDEVELTCQATGYPLAEVSWPNVSVPANTSHSRTPEGLYQVTSVLRLKPPPGRNFSCVFWNTHVRELTLASIDLQSQMEPRTHPTWLLHIFIPFCIIAFIFIATVIALRKQLCQKLYSSKDTTKRPVTTTKREVNSAI

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Detailed Information

The PD-L2 gene encodes Programmed Death-Ligand 2 (PD-L2), a member of the B7 family of immune regulatory molecules. Structurally, the PD-L2 protein contains extracellular IgV and IgC domains, a transmembrane domain, and a short intracellular tail. Compared to its homolog PD-L1, PD-L2 displays more restricted expression, predominantly found on dendritic cells, macrophages, and B cells, and is induced by Th2-type cytokines such as IL-4 and IL-13.

PD-L2 exhibits dual immunoregulatory roles:

Inhibitory signaling:Upon binding PD-1, PD-L2 suppresses TCR signaling and reduces IFN-γ production.
Co-stimulatory signaling: Through receptors independent of PD-1, such as RGMb, PD-L2 promotes Th2 differentiation and IL-10 secretion.

This functional duality enables PD-L2 to either inhibit antitumor immunity or maintain immune homeostasis, depending on the microenvironmental context.

Figure 1. The diagram shows the PD-L1 encoding gene CD274 and CD273. (Fan Z, et al., 2022)

Disease Associations and Clinical Implications

An Inflammatory Amplifier in Systemic Lupus Erythematosus (SLE)

A study conducted by Soochow University demonstrated that PD-L2 expression on peripheral blood mononuclear cells (PBMCs) from SLE patients was significantly higher than in healthy controls and positively correlated with disease activity index (SLEDAI, r = 0.62). Mechanistically, PD-L2 enhances B cell TLR7 signaling to promote anti-dsDNA antibody production and aggravates inflammation by inhibiting Treg differentiation. PD-L2 expression in active SLE patients was 2.3 times higher than in those in remission, highlighting its potential as a biomarker for disease activity.

A Co-Conspirator in Tumor Immune Evasion

Although PD-L2 expression is generally lower than PD-L1 in solid tumors, its immunosuppressive effect is more potent:

Affinity difference: The dissociation constant (KD) of PD-L2 binding to PD-1 is 1.0 nM, which is approximately 8,200 times higher than that of PD-L1.
Resistance relevance: In melanoma patients resistant to anti-PD-1 therapy, PD-L2⁺ tumor-associated macrophage (TAM) infiltration increases threefold.

Notably, PD-L2 is highly expressed in follicular lymphoma (FL), with a positivity rate of up to 70%, and is associated with resistance to PD-1 blockade. It achieves this by binding to RGMb receptors on dendritic cells, activating the IDO pathway, and promoting T cell exhaustion.

Therapeutic Potential

Development of Antagonists:

PD-L2/TLR7 bispecific antibodies have shown the ability to reduce anti-dsDNA antibody titers in primate models of SLE.
RGMb-blocking peptides can relieve PD-L2-mediated T cell inhibition and enhance the efficacy of anti-PD-1 therapies.

Application of Agonists: The soluble PD-L2-Fc fusion protein (AM-3301) demonstrated good tolerability in a Phase II trial for rheumatoid arthritis, with a 42% improvement in DAS28 scores.

Challenges and Controversies

Conflicting biomarker roles: While PD-L2 promotes inflammation in SLE, it plays a protective role in ulcerative colitis by inducing regulatory B cells.
Lack of standardized detection: PD-L2 expression is sensitive to sample handling (e.g., freeze-thaw cycles reduce detection rates by 35%) and the specificity of antibody clones (e.g., clone 176611 shows insufficient specificity).

Precision and Challenges in Targeted Therapy

PDGFRA, PDGFRB, and PD-L2 each represent key targets across receptor tyrosine kinase and immune checkpoint categories, with distinct therapeutic implications:

PDGFRA: The D842V mutation has reshaped GIST treatment paradigms; Avapritinib has rendered this resistance-associated mutation a druggable target.
PDGFRB: Fusion genes serve as rare but actionable drivers in hematologic malignancies, where long-term disease control is achievable with low-dose TKIs.
PD-L2: Its dual regulatory pathways highlight the complexity of the immune microenvironment, necessitating the development of ligand-specific blocking agents.

Advances in cryo-EM and single-cell sequencing technologies are likely to accelerate the development of highly personalized and precise therapeutic approaches.

References:

Fan Z, Wu C, Chen M, et al. The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation. Acta Pharm Sin B. 2022 Mar;12(3):1041-1053.
Zak KM, Grudnik P, Magiera K, et al. Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2. Structure. 2017 Aug 1;25(8):1163-1174.

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