Gvhd Increases Apoptosis of CD8+, but Not CD4+, T Cells Expanded by Vaccines but Is Not Dependent on Fas Ligand
Bibliographic record
Abstract
Abstract Abstract 2098 Donor lymphocyte infusions (DLIs) administered following allogeneic blood and marrow transplantation (alloBMT) can enhance T cell reconstitution through homeostatic peripheral expansion (HPE), but can also cause graft-versus-host-disease (GVHD). Vaccines are a strategy to skew T cells toward a “third-party” tumor antigen, but it is not clear if the effects of GVHD on vaccine-responding T cells is equivalent to the effects on alloantigen-reactive polyclonal T cells. Previous work by others has demonstrated “bystander” effects of GVHD causing activation-induced cell death through the Fas pathway on polyclonal T cells; however, the impact of GVHD on T cells expanded by a vaccine expressing a third-party nonalloantigen remains unclear. T cell depleted (TCD) minor histocompatibility antigen (mHA)-mismatched alloBMT (CD45.1+ B6 –> CD45.1+/CD45.2+ B6 × C3H.SW) was followed by a CD45.1+ B6 DLI on day +14 to induce GVHD. CD45.2+ B6 Rag2-/- T cell receptor transgenic (TCRTg) CD4+ or CD8+ T cells specific for epitopes derived from the male histocompatibility antigen complex (HY) were administered on day +28 with an HY-expressing male dendritic cell vaccine to determine the impact of the allogeneic environment on the persistence, proliferation and survival of vaccine-responding T cells. Despite the fact that syngeneic and allogeneic recipients had similar degrees of lymphopenia, the absolute number of CD4+ and CD8+ TCRTg T cells was decreased 5 and 7 days respectively after adoptive transfer and vaccination in alloBMT recipients compared to syngeneic recipients (p < 0.05). To determine the mechanism of decreased persistence of the TCRTg T cells, proliferation was measured by assessing dilution of CFSE and apoptosis was measured by FACS analysis for Annexin V. Importantly, since both the CD4+ and CD8+ TCRTg T cells do not undergo HPE, all proliferation has to be antigen-driven. Neither CD4+ nor CD8+ TCRTg T cells proliferated in the absence of HY vaccine following alloBMT, confirming lack of bystander proliferation. Interestingly, both CD4+ (p < 0.01) and CD8+ (p < 0.05) TCRTg T cells undergo less vaccine-induced proliferation after alloBMT compared to syngeneic recipients. The amount of CD8+ TCRTg T cell apoptosis following vaccination was higher in allogeneic recipients (p < 0.05), but there was no difference in CD4+ TCRTg T cell apoptosis. Surprisingly, using a DLI from Fas ligand-deficient B6 (gld) donors on day +14 was sufficient to induce GVHD but did not prevent CD8+ TCRTg T cell apoptosis. Thus, diminished vaccine responses during GVHD appear to result in part from impaired CD8+ and CD4+ T cell vaccine-driven proliferation, but there is an additional contribution on CD8+ T cell apoptosis that is not dependent on recognition of alloantigen or the Fas-Fas ligand pathway. Disclosures: No relevant conflicts of interest to declare.
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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) | 0.003 | 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".