Follicular T cells mediate donor-specific antibody and rejection after solid organ transplantation

Mohammed, Mostafa T.; Cai, Shanshan; Hanson, Benjamin L.; Zhang, Hengcheng; Clement, Rachel L.; Daccache, Joe; Cavazzoni, Cecília B.; Blazar, Bruce R.; Alessandrini, Alessandro; Rennke, Helmut G.; Chandraker, Anil; Sage, Peter T.

doi:10.1111/ajt.16484

Cited by 29 publications

(40 citation statements)

References 35 publications

(39 reference statements)

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“…Tfh cells optimize early SARS-CoV-2-specific germinal center responses after protein vaccination The precise roles of Tfh cells in mediating clonal dynamics within GCs have remained poorly understood due to a lack of tools. We recently developed a ''Tfh-DTR'' mouse to delete Tfh cells with administration of diphtheria toxin (DT) (Mohammed et al, 2021). The Tfh-DTR contains both Cd4 Cre and Cxcr5 LoxSTOPLoxDTR alleles, which posits the DT receptor (DTR) on the surface of CD4 + T cells expressing CXCR5, including Tfh cells.…”

Section: Sars-cov-2 Spike Protein Vaccination Generates Robust Germin...mentioning

confidence: 99%

“…The Tfh-DTR contains both Cd4 Cre and Cxcr5 LoxSTOPLoxDTR alleles, which posits the DT receptor (DTR) on the surface of CD4 + T cells expressing CXCR5, including Tfh cells. Tfr cells will also be deleted in the Tfh-DTR mouse, but we refer to it as the Tfh-DTR for simplicity (Mohammed et al, 2021). We vaccinated control (Cd4 Cre Cxcr5 wt ) or Tfh-DTR (Cd4 Cre Cxcr5 LoxSTOPLoxDTR ) mice with the SARS-CoV-2 Spike protein vaccine, administered DT, and assessed responses on day 14.…”

Section: Sars-cov-2 Spike Protein Vaccination Generates Robust Germin...mentioning

confidence: 99%

“…The role of Tfr cells in controlling GC responses to foreign antigens has remained controversial, with some studies finding that Tfr cells limit, whereas others promote, GC B cells (Sage and Sharpe, 2020). To study the role of Tfr cells in regulating GC clonal dynamics, we used Tfr-DTR mice, which allows deletion of Tfr cells with DT (Clement et al, 2019;Mohammed et al, 2021). We vaccinated control (Foxp3 Cre Cxcr5 wt ) or Tfr-DTR (Foxp3 Cre Cxcr5 LoxSTOPLoxDTR ) mice with the SARS-CoV-2 Spike protein vaccine and administered DT to delete Tfr cells.…”

Section: Tfr Cells Promote Sars-cov-2-specific Gc Responses By Limiti...mentioning

confidence: 99%

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Follicular T cells optimize the germinal center response to SARS-CoV-2 protein vaccination in mice

et al. 2022

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Follicular helper T (Tfh) cells promote, whereas follicular regulatory T (Tfr) cells restrain, germinal center (GC) reactions. However, the precise roles of these cells in the complex GC reaction remain poorly understood. Here, we perturb Tfh or Tfr cells after SARS-CoV-2 spike protein vaccination in mice. We find Tfh cells promote the frequency and somatic hypermutation (SHM) of Spike-specific GC B cells and regulate clonal diversity. Tfr cells similarly control SHM and clonal diversity in the GC, but do so through limiting clonal competition. In addition, deletion of Tfh or Tfr cells during primary vaccination results in changes in SHM after vaccine boosting. Aged mice, which have altered Tfh and Tfr cells, have lower GC responses presenting a bimodal distribution of SHM. Together, these data demonstrate GC responses to SARS-CoV-2 spike protein vaccines require a fine balance of positive and negative follicular T cell help to optimize humoral immunity.

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Section: Sars-cov-2 Spike Protein Vaccination Generates Robust Germin...mentioning

confidence: 99%

Section: Sars-cov-2 Spike Protein Vaccination Generates Robust Germin...mentioning

confidence: 99%

Section: Tfr Cells Promote Sars-cov-2-specific Gc Responses By Limiti...mentioning

confidence: 99%

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Follicular T cells optimize the germinal center response to SARS-CoV-2 protein vaccination in mice

et al. 2022

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“…We also performed allogeneic kidney transplantation in Tfr-DTR mice to assess the roles of Tfr cells in controlling AMR. Although we found that Tfr cells can limit IgG DSA using splenocyte alloantigen challenge models, we did not find substantial differences in severity of AMR during kidney transplantation when Tfr cells were deleted ( Mohammed et al, 2021 ). However, one caveat to these experiments is that a full MHC mismatch kidney transplant model was used in which rejection rapidly occurs within 3 weeks.…”

Section: T Follicular Regulatory (Tfr) Cellsmentioning

confidence: 68%

“…We recently developed a pre-clinical allogeneic kidney transplant model to assess the roles of Tfh and Tfr cells in controlling DSA and AMR. Using a Tfh-DTR model in which Tfh cells were deleted during transplantation we found that Tfh cells were essential for IgG DSA as well as AMR after kidney transplantation ( Mohammed et al, 2021 ). We also performed allogeneic kidney transplantation in Tfr-DTR mice to assess the roles of Tfr cells in controlling AMR.…”

Section: T Follicular Regulatory (Tfr) Cellsmentioning

confidence: 99%

Regulation of Alloantibody Responses

Chong

Sage

Alegre

2021

Front. Cell Dev. Biol.

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The control of alloimmunity is essential to the success of organ transplantation. Upon alloantigen encounter, naïve alloreactive T cells not only differentiate into effector cells that can reject the graft, but also into T follicular helper (Tfh) cells that promote the differentiation of alloreactive B cells that produce donor-specific antibodies (DSA). B cells can exacerbate the rejection process through antibody effector functions and/or B cell antigen-presenting functions. These responses can be limited by immune suppressive mechanisms mediated by T regulatory (Treg) cells, T follicular regulatory (Tfr) cells, B regulatory (Breg) cells and a newly described tolerance-induced B (TIB) cell population that has the ability to suppress de novo B cells in an antigen-specific manner. Transplantation tolerance following costimulation blockade has revealed mechanisms of tolerance that control alloreactive T cells through intrinsic and extrinsic mechanisms, but also inhibit alloreactive B cells. Thus, the control of both arms of adaptive immunity might result in more robust tolerance, one that may withstand more severe inflammatory challenges. Here, we review new findings on the control of B cells and alloantibody production in the context of transplant rejection and tolerance.

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Desensitization Strategies for Donor-Specific Antibodies in HLA-Mismatched Stem Cell Transplantation Recipients: What We Know and What We Do Not Know

Zhou,

Chen,

Huang

et al. 2024

Oncol Ther

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In human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation settings, donor-specific anti-HLA antibodies (DSAs) can independently lead to graft failure, including both primary graft rejection and primary poor graft function. Although several strategies, such as plasma exchange, intravenous immunoglobulin, rituximab, and bortezomib, have been used for DSA desensitization, the effectiveness of desensitization and transplantation outcomes in some patients remain unsatisfactory. In this review, we summarized recent research on the prevalence of anti-HLA antibodies and the underlying mechanism of DSAs in the pathogenesis of graft failure. We mainly focused on desensitization strategies for DSAs, especially novel methods that are being investigated in the preclinical stage and those with promising outcomes after preliminary clinical application.

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Follicular T cells mediate donor-specific antibody and rejection after solid organ transplantation

Cited by 29 publications

References 35 publications

Follicular T cells optimize the germinal center response to SARS-CoV-2 protein vaccination in mice

Follicular T cells optimize the germinal center response to SARS-CoV-2 protein vaccination in mice

Regulation of Alloantibody Responses

Desensitization Strategies for Donor-Specific Antibodies in HLA-Mismatched Stem Cell Transplantation Recipients: What We Know and What We Do Not Know

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