Hypoxia and IL-15 Cooperate to Induce Perforin Expression by CD8 T Cells and Promote Damage to the Skin in Murine Cutaneous Leishmaniasis
Bibliographic record
Abstract
Cutaneous leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania, and although parasites influence disease severity, cytotoxic CD8 T-cell responses mediate damage to the infected skin. We found that the cytotoxic protein perforin was expressed in CD8 T cells only upon recruitment to Leishmania-infected skin, suggesting that lesional inflammatory cues induced perforin. In this study, using a mouse model of Leishmania major infection, we demonstrated that the expression of perforin was driven by a combination of hypoxia and IL-15, both of which are microenvironmental signals present within Leishmania-infected skin. We also demonstrated that the major sources of Il15 mRNA in cutaneous leishmaniasis lesions are neutrophils and macrophages and that macrophages exposed to hypoxia in vitro produce more Il15. Because perforin is only present in lesions, we reformulated a small-molecule perforin inhibitor for topical application and found that local inhibition of perforin is sufficient to ameliorate disease in established cutaneous leishmaniasis. Thus, topical perforin inhibition may be considered a therapeutic strategy for patients with cutaneous leishmaniasis and other inflammatory skin diseases where cytotoxic CD8 T cells contribute to disease pathogenesis.
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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 | 0.000 |
| 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".