Unveiling the Regulatory Role of CD8+ T-Cells in the Pathogenesis and Effective Steroid Treatment in ITP
Bibliographic record
Abstract
Abstract Background:Immune thrombocytopenia (ITP) is a common bleeding disorder. Autoantibodies against platelet GPIIbIIIa (integrin αIIbβ3, 70-80%) and GPIb-complex (20-40%) are considered to be the major mechanism leading to autologous platelet destruction. Recent studies demonstrated that in addition to autoantibodies, CD8+ cytotoxic T cells (CTLs) also contribute to thrombocytopenia, either through direct cytotoxicity against platelets or megakaryocytes. However, the roles of CD8+ regulatory T cells (Tregs) in ITP have not been adequately explored. Methods and Results: We developed the first animal models of steroid treatment in ITP, encompassing both the passive and active forms. In the passive model, we injected anti-β3 antibodies to induce transient antibody mediated thrombocytopenia. We found that a single intraperitoneal (IP) injection of steroids post-antibody injection was effective at rescuing platelet counts. We also adapted an active model of ITP whereby wild-type (WT) BALB/c mice were transfused with splenocytes from WT platelet immunized β3-/-mice. This model encompasses both antibody and cell-mediated ITP resulting in sustained thrombocytopenia. In this model, we found steroid treatment (prednisone and dexamethasone) administered daily either orally or through IP-injection were equally efficacious at ameliorating thrombocytopenia. Furthermore, immunophenotyping and cytokine analysis reveal a similar profile as reported of human ITP patients responsive to steroid treatments. Thus, successful steroid treatments in these animal models are representative of the therapeutic effects of steroid treatments seen in human ITP patients. To study the role of CD8+ T cells in the pathogenesis and response to steroid treatments in ITP, we depleted CD8+ T cells from splenocytes prior to its transfusion into WT mice. Unexpectedly,we found CD8+ T cell depleted splenocyte (lacking in CTL cells) engrafted mice had lower, but not higher, platelet counts and were less responsive to dexamethasone (DEX) treatment compared to non-depleted engrafted mice. Furthermore, in the passive ITP model, depletion of CD8+ T cells from mice prior to injection of anti-β3 antibodies resulted in more severe thrombocytopenia, compared with non-depleted mice. Conversely, transfusion of either antigen-primed CD8+ (isolated from immunized β3-/- splenocytes) or WT/β3-/- naïve CD8+ T cells alone was sufficient to rescue platelet counts and improve response to DEX in the passive ITP model. These results indicate for the first time that CD8+ T cells from both antigen-primed and naïve populations play a protective role in attenuating platelet clearance. In further support of these observations, we detected significant increased populations of both CTLs and CD8+ Tregs including, CD8+CD25+Foxp3+, CD8+CD103+, CD8+CD122+ and CD8+CD28- in the blood, and spleen of immunized β3-/- mice. Interestingly, the CD8+ Tregs populations were further increased while CTL population decreased following DEX treatment in the active ITP model. In vitro splenocyte cultures were used to explore putative regulatory mechanisms of CD8+ Tregs. It was found that antigen-primed CD8+ Tregs exerted significantly stronger inhibition CD4+ T- and CD19+ B cell proliferation, platelet apoptosis, and platelet associated IgG production in the presence of platelet antigens, while both antigen-primed and naïve CD8+ Tregs could effectively inhibit macrophage mediated phagocytosis of anti-β3 opsonized platelets. Conclusion: To the best of our knowledge, these are the first reported animal models of effective steroid treatment of ITP. Utilizing these models we uncovered a previously unidentified regulatory role of CD8+ T cells in both ITP and steroid treatment. The increased populations of various CD8+ Tregs following β3-/- immunization exerted a significant inhibitory function against other immune-cell mediated anti-platelet responses. In addition, therapeutic administration of both antigen-primed and naïve CD8+ T cells were able to rescue platelet counts in the passive ITP model. This suggests that CD8+ Treg may play a predominantly protective role in ITP. These data provides significant insights into the understanding of immunopathogenesis of ITP, which may be important in designing effective therapy including the potential usage of CD8+ Tregs as a cellular target in the treatment of ITP. 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) | 0.001 | 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".