Background: T cells are the master regulators of the immune system and represent critical targets for immune therapies. In this study we aimed to understand the mechanisms by which an antibody targeting the TCR Β-chain can selectively control antigen (Ag) specific immune responses. Methods/Results: To test the selectivity of anti-TCRΒ mAb in controlling Ag-responding cells, we adoptively transferred CFSE-labeled OT-II cells into wild type C57BL/6 mice and provided 5¯o;g of OVA peptide to stimulate these transgenic T cells. Anti-TCRΒ mAb treatment reduced 98% of Ag-responding OT-II T cells when compared to untreated controls. At the same time the number of non-responding T cells in these mice were reduced by only 70%. In an acute model of type 1 diabetes, a single injection of anti-TCRΒ mAb into RIP-OVA mice completely inhibited disease development that was induced by adoptively transferred OVA-specific T cells. Transient high dose therapy with anti-TCRΒ mAb also significantly prolonged Balb/c skin allograft survival in C57BL/6 recipients (68±5days) compared to untreated controls (9±5days; p<0.05). To demonstrate that these effects were Ag-specific, Rag1-/- mice were adoptively transferred with Foxp3/GFP splenocytes and transplanted with allogeneic BALB/c skins followed by transient anti-TCRΒ mAb treatment. All skin allografts survived >140days compared to untreated controls which were rejected within 10days. C3H skins transplanted onto these recipients bearing BALB/c skin transplants for 120days were rejected within 10days. In order to understand the effects of the anti-TCRΒ mAb on T cells we isolated total RNA from CD4+ and CD8+ T cells and performed qPCR array to measure the transcriptional levels of different regulatory proteins in T cells. The results revealed that anti-TCRΒ mAb engagement of T cells reduced expression of several proteins involved in T cell responses, including Foxo1, Foxo3, Runx1, and Rnf-128 in both CD4+ and CD8+ T cells. In addition, the expression of only one protein Cbl-b, an E3 ubiquitin ligase, was enhanced in CD4+ T cells upon treatment with anti-TCRΒ mAb. Conclusion: Therapy with anti-TCRΒ mAb abrogates predominantly donor-reactive rather than naive T cells. Since this correlates with a unique alteration of transcriptional patterns in T cells, such modified signaling results in a more selective depletion of Ag-responding T cells.
To cite this abstract in AMA style:Schroder P, Khattar M, Deng R, Baum C, Mierzejewska B, Stepkowski S. Antibody Targeting the TCR β-Chain Selectively Abrogates Antigen-Specific T Cell Responses by Modulating T Cell Transcriptional Patterns [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/antibody-targeting-the-tcr-chain-selectively-abrogates-antigen-specific-t-cell-responses-by-modulating-t-cell-transcriptional-patterns/. Accessed October 27, 2020.
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