Ablation of BATF Alleviates Transplant Rejection via Abrogating the Effector Differentiation and Memory Responses of CD8+ T Cells
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TLDR
It is found that BATF is highly expressed in graft-infiltrating CD8+ T cells, and its ablation in CD8- T cells significantly prolonged skin allograft survival in a fully MHC-mismatched transplantation model and may be an attractive therapeutic approach to promote transplant acceptance.Abstract:
Allogeneic CD8+ T cells are prominently involved in allograft rejection, but how their effector differentiation and function are regulated at a transcriptional level is not fully understood. Herein, we identified the basic leucine zipper ATF-like transcription factor (BATF) as a key transcription factor that drives the effector program of allogeneic CD8+ T cells. We found that BATF is highly expressed in graft-infiltrating CD8+ T cells, and its ablation in CD8+ T cells significantly prolonged skin allograft survival in a fully MHC-mismatched transplantation model. To investigate how BATF dictates allogeneic CD8+ T cell response, BATF–/– and wild-type (WT) CD8+ T cells were mixed in a 1:1 ratio and adoptively transferred into B6.Rag1 –/– mice 1 day prior to skin transplantation. Compared with WT CD8+ T cells at the peak of rejection response, BATF–/– CD8+ T cells displayed a dysfunctional phenotype, evident by their failure to differentiate into CD127–KLRG1+ terminal effectors, impaired proliferative capacity and production of pro-inflammatory cytokines/cytotoxic molecules, and diminished capacity to infiltrate allografts. In association with the failure of effector differentiation, BATF–/– CD8+ T cells largely retained TCF1 expression and expressed significantly low levels of T-bet, TOX, and Ki67. At the memory phase, BATF-deficient CD8+ T cells displayed impaired effector differentiation upon allogeneic antigen re-stimulation. Therefore, BATF is a critical transcriptional determinant that governs the terminal differentiation and memory responses of allogeneic CD8+ T cells in the transplantation setting. Targeting BATF in CD8+ T cells may be an attractive therapeutic approach to promote transplant acceptance.read more
Citations
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Journal ArticleDOI
An Immune Atlas of T Cells in Transplant Rejection: Pathways and Therapeutic Opportunities.
S. Short,Guido Lewik,Fadi Issa +2 more
TL;DR: In this article , the authors investigated the role of regulatory subsets in acute cellular rejection and their potential to promote tolerance of allografts in the context of transplantation, revealing new avenues of therapeutic intervention for the prevention of rejection.
Journal ArticleDOI
An Immune Atlas of T Cells in Transplant Rejection: Pathways and Therapeutic Opportunities
TL;DR: In this article , the authors investigated the role of regulatory subsets and their potential to promote tolerance of allografts in the context of transplantation, revealing new avenues of therapeutic intervention for the prevention of rejection.
References
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The AP-1 transcription factor Batf controls TH17 differentiation
Barbara U. Schraml,Kai Hildner,Wataru Ise,Wan-Ling Lee,Whitney A.-E. Smith,Ben Solomon,Gurmukh Sahota,Julia Sim,Ryuta Mukasa,Saso Cemerski,Robin D. Hatton,Gary D. Stormo,Casey T. Weaver,John H. Russell,Theresa L. Murphy,Kenneth M. Murphy +15 more
TL;DR: It is shown that Batf is required for the differentiation of IL17-producing T helper (TH17) cells, and it is demonstrated that the AP-1 protein BATF has a critical role in TH17 differentiation.
Journal ArticleDOI
Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients.
Alice O. Kamphorst,Rathi N. Pillai,Shu Yang,Tahseen H. Nasti,Rama Akondy,Andreas Wieland,Gabriel Sica,Ke Yu,Lydia Koenig,Nikita Patel,Madhusmita Behera,Hong Wu,Megan McCausland,Zhengjia Chen,Chao Zhang,Fadlo R. Khuri,Taofeek K. Owonikoko,Rafi Ahmed,Suresh S. Ramalingam +18 more
TL;DR: Analysis of changes in peripheral blood T cells from lung cancer patients receiving immunotherapy blocking the PD-1 inhibitory pathway suggests that peripheral blood analysis may provide valuable insights into NSCLC patients’ responses toPD-1–targeted therapies.
Journal ArticleDOI
Antigen-driven effector CD8 T cell function regulated by T-bet.
TL;DR: It is reported that the transcription factor T-bet, known to regulate Th cell differentiation, also controls the generation of the CD8+ cytotoxic effector cell, and mice lacking T-Bet responded poorly to infection with lymphocytic choriomeningitis virus.
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The Chemokine Receptor CX3CR1 Defines Three Antigen-Experienced CD8 T Cell Subsets with Distinct Roles in Immune Surveillance and Homeostasis
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TL;DR: A subset of CX3CR1int Tmem cells present unique phenotypic, homeostatic, and migratory properties, and it is proposed that tpm cells are chiefly responsible for the global surveillance of non-lymphoid tissues.
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BATF–JUN is critical for IRF4-mediated transcription in T cells
Peng Li,Rosanne Spolski,Wei Liao,Lu Wang,Theresa L. Murphy,Kenneth M. Murphy,Warren J. Leonard +6 more
TL;DR: It is revealed that IRf4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription.