Structural, functional, and evolutionary differences between PD-L1 and PD-L2
Bibliographic record
Abstract
Abstract The PD-1/PD-L1/PD-L2 axis is a critical immune checkpoint that tips immune responses towards tolerance. This axis has been heavily targeted in cancer immunotherapy with monoclonal antibodies, which block receptor-ligand interactions. PD-L1 is constitutively expressed at low levels and is induced on nearly all tissues upon IFN-gamma signaling. In contrast, PD-L2 expression is restricted mainly to antigen presenting cells (APC)s, such as dendritic cells and macrophages. PD-L2 has a 4-fold stronger affinity for PD-1 than does PD-L1. It has been proposed that W110 of PD-L2 accounts for this affinity difference; the corresponding PD-L1 residue is A121. To test this hypothesis, we produced, in a mammalian expression system, a set of PD-L1 and PD-L2 proteins with the W and A swapped, and studied their binding to PD-1 using surface plasmon resonance. Surprisingly, rather than decreasing affinity as expected, a W110A substitution improved affinity by decreasing the off-rate. We propose a novel structural mechanism for PD-L2’s affinity advantage, one that interestingly emerged upon the evolution of placental mammals. We examined the functional effect that these structural alterations have on the PD-Ligands ability to inhibit T cell activation and found a correlation. Additionally, we discovered that PD-Ligands homo- and hetero-dimerize in a manner similar to other B7-family members, with PD-L2 displaying the strongest homo-dimerization. Collectively, these data support our hypothesis that PD-L2 expression on APCs provides an inhibitory advantage, one that may heighten the tolerogenic hurdle that an immune response must overcome during the priming phase.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".