The Restorative Effect of Flt3-Ligand and IL-7 On CD4+ T Cell Homeostatic Proliferation During Graft-Versus-Host Disease
Bibliographic record
Abstract
Allogeneic hematopoietic stem cell transplantation (SCT) is the best treatment for numerous types of hematological malignancies. However, graft-versus-host disease (GVHD) is the major cause of morbidity and mortality and its effect on T cell regeneration greatly exacerbates the immunodeficiency normally associated with this treatment. As a result, patients with GVHD are profoundly lymphopenic and T cell reconstitution typically takes several months or years. We previously reported that IL7Ra-/- mice have a peripheral lymphoid niche that is highly permissive for homeostatic proliferation (HP) of CD4+ T cells. Given that CD4+ T cells regeneration is impaired during GVHD, we hypothesized that using IL7Ra-/- bone marrow (BM) might improve their recovery in GVHD hosts. To study the impact of GVHD on the peripheral niche regulating CD4 HP, we used the mouse model B6 into B6D2F1. Since IL7Ra-/- DCs support efficiently HP of naïve CD4+ T cells during lymphopenia, we used BM stem cells from B6IL7Ra-/- mice and induced GVHD by adding 1x106 B6 T cells. Finally, to understand the impact of GVHD on HP, we transferred CFSE labelled anti-HY CD4+ T cells (Marilyn) into GVHD hosts and measured their homeostatic proliferation 7 days later. In non GVHD hosts, Marilyn T cells underwent robust HP while they completely failed in GVHD hosts. Absence of HP during GVHD was associated with a severe depletion of all DC subsets, including myeloid, lymphoid and pDCs. Low number of DCs during GVHD was in part due to their elimination by GVHD T cells but most importantly to a myelosuppression affecting DC production from BM progenitor cells. Interestingly, treatment of GVHD mice with FLT3 ligand (FL) significantly increased the number of DCs, yet it was insufficient for restoring CD4 HP. Given that stromal cells and IL7 mRNA levels were also diminished in GVHD hosts, we provided both FL and IL-7 to GVHD mice and significantly restored HP of Marilyn CD4+ T cells in this setting. Thus far, our data support a model wherein loss of CD4 HP during GVHD relates to lower numbers of DC and diminished systemic IL7.
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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".