PD-1 Pathway Dynamics in Autoimmune Disorders

The programmed cell death protein-1 (PD-1) pathway constitutes a central regulatory axis in maintaining immune tolerance and preventing self-reactivity. Engagement of PD-1 on T lymphocytes by its ligands PD-L1 or PD-L2 delivers inhibitory signals that temper T-cell activation, promote T-cell exhaustion in chronic antigenic settings and support regulatory T-cell (Treg) differentiation. In diverse autoimmune disorders—including rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis—alterations in PD-1 expression, the balance of membrane-bound versus soluble PD-1, and the tissue distribution of ligands contribute to pathogenesis. Elevated soluble PD-1 can act as a decoy, impairing inhibitory signalling, whereas reduced PD-L1 expression in affected tissues sustains inflammatory T-cell responses. Conversely, strategies to agonise PD-1 or enhance ligand availability have shown promise in preclinical models, dampening Th1 and Th17 effector programmes and restoring homeostasis. The pathway’s dynamics vary by disease stage and tissue context: synovial versus peripheral blood compartments in arthritis display distinct patterns of receptor and ligand expression; central nervous system lesions reveal altered endothelial and glial ligand presentation; and circulating biomarkers of PD-1 engagement correlate with disease activity scores. Understanding these nuances informs biomarker development, guides patient stratification and underpins novel immunomodulatory therapies aimed at re-establishing tolerance without broad immunosuppression.

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PD-1 Pathway Dynamics in Autoimmune Disorders publication trend

The graph below shows the total number of articles in pd-1 pathway dynamics in autoimmune disorders across all publications each year (not limited to Nature Index journals).

Technical terms

PD-1: A surface receptor on T cells that, upon ligand binding, transmits inhibitory signals to limit T-cell activation and promote immune tolerance.

PD-L1/PD-L2: Ligands expressed on antigen-presenting and non-haematopoietic cells that engage PD-1 to downregulate immune responses.

Immune checkpoint: A regulatory pathway, often comprising receptor–ligand pairs, that modulates the amplitude and duration of immune activation.

Treg cell: A subset of CD4+ T cells specialised in suppressing effector responses and maintaining peripheral tolerance.

Th1/Th17 cells: Distinct effector CD4+ T-cell lineages characterised by production of interferon-γ (Th1) or interleukin-17 (Th17), both implicated in autoimmune inflammation.

References

1. Advances in immune checkpoint-based immunotherapies for multiple sclerosis: rationale and practice. Cell Communication and Signaling (2023).
2. The effect of combining PD-1 agonist and low-dose Interleukin-2 on treating systemic lupus erythematosus. Frontiers in Immunology (2023).
3. Comprehensive Co-Inhibitory Receptor (Co-IR) Expression on T Cells and Soluble Proteins in Rheumatoid Arthritis. Cells (2024).
4. Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathways. Arthritis Research & Therapy (2015).
5. Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression. PLOS ONE (2018).
6. Human brain endothelial cells endeavor to immunoregulate CD8 T cells via PD-1 ligand expression in multiple sclerosis. Journal of Neuroinflammation (2011).
7. The Diverse Function of PD-1/PD-L Pathway Beyond Cancer. Frontiers in Immunology (2019).
8. Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression. Frontiers in Immunology (2018).
9. Synovial T cell hyporesponsiveness to myeloid dendritic cells is reversed by preventing PD-1/PD-L1 interactions. Arthritis Research & Therapy (2014).