Evidence for Cooperativity in the Rejection of Cardiac Grafts Mediated by CD4+ TCR Tg T Cells Specific for a Defined Allopeptide

Honjo, Kazuhito; Xu, Xiaohong; Kapp, Judith A.; Bucy, R. Pat

doi:10.1046/j.1600-6143.2004.00596.x

Cited by 29 publications

(32 citation statements)

References 26 publications

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“…A) . B6.K d animals are C57BL/6 mice transgenic for H2.K d . Interestingly, there was not an absolute correlation between graft rejection and alloantibody production as none of the mice receiving MR1 alone had detectable serum anti‐K d IgG even though they rejected the graft (Fig.…”

Section: Resultsmentioning

confidence: 97%

Transitional‐2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival

et al. 2014

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IntroductionThere is growing evidence that in some circumstances B cells contribute to the maintenance of transplant tolerance [1,2], as well as promoting chronic allograft responses [3][4][5]. In mice, anti-CD20 depletion has been reported to accelerate skin graft rejection [3], and anti-CD45RB-induced tolerance to heart transplants requires Correspondence: Prof. Giovanna Lombardi e-mail: giovanna.lombardi@kcl.ac.uk the presence of B cells [6]. In rats, long-term allograft tolerance is characterized by an accumulation of B cells expressing genes associated with tolerance [7].We have recently reported that immunosuppressant-free transplant patients who were spontaneously tolerant to transplanted HLA-mismatched kidneys had a "B-cell signature" [8]. Compared to healthy controls and nontolerant patients, tolerant recipients * These authors contributed equally to this study. * * These authors contributed equally to this study as senior authors.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 844Aurélie Moreau et al. Eur. J. Immunol. 2015. 45: 843-853 upregulated genes associated with B-cell function in peripheral blood. Further studies have shown that drug-free tolerant patients maintain transitional B-cell numbers in their peripheral blood at the same levels as healthy individuals, and at higher numbers than stable patients on immunosuppressant or chronic rejectors [9,10]. As previously reported, these transitional B cells may represent a regulatory subset that actively regulates the alloresponse [11]. Regulatory B (Breg) cells have been shown to be important in the maintenance of tolerance in a number of mouse models of autoimmunity [12,13] [17,18]. T2 B cells were transiently expanded in mice tolerized by donor splenocyte transfusion (DST) and anti-CD40L treatment. T2 B cells isolated from tolerized mice, but not from naïve mice, were able to prolong skin graft survival in vivo and suppress T-cell cytokine production in vitro. The ability of tolerized B cells to prolong graft survival was antigen specific and involved cooperation with Treg cells. IL-10 production did not correlate with suppressive capacity, however T2 isolated from tolerized mice displayed enhanced survival in vivo, upregulated TIM-1 expression, but lost CD86 expression. ResultsTransfer of tolerized B cells prolongs skin allograft survival in an antigen-specific manner C57BL/6 mice can be rendered tolerant to skin transplants from MHC class I mismatched C57BL/6. (Fig. 1D).Neither transfer of splenic non-B cells nor B cells from naïve mice, previously shown to be effective in autoimmune models but not effective in transplantation models [14,15,21], was able to prolong graft survival. Transfer of B cells from tolerant mice also significantly reduced the amount of IgG anti-K d alloantibody present in the serum of recipient mice ( Fig. 1E and F). In addition, the transfer of 10 × 10 6 tolerized B cells was able to prolong skin graft survival significantly longer than transfer of 2 × 10 6 tolerized B cells (Fig. 1G). We next t...

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Section: Resultsmentioning

confidence: 97%

Transitional‐2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival

et al. 2014

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“…Surface phenotyping of the K d 54-68 /I-A b tetramer pos CD4 T cell population revealed that the percentage of antigen-experienced CD44 hi CD4 T cells was comparable 5 weeks after transplantation with a BALB/c or bm12.Kd.IE heart allograft but that the antigen-experienced CD4 T cells in recipients of a bm12.Kd.IE heart graft were predominantly CD44 hi CCR7 lo CD62L lo effector memory, whereas those in BALB/c heart-grafted recipients were more skewed toward CD44 hi CCR7 hi CD62L hi central memory (Figure 6D). To assess the functional consequences of this difference, T-cell-deficient Tcrbd −/− C57BL/6 mice were reconstituted with CD4 T cells purified from recipients of bm12.Kd.IE or BALB/c heart grafts and the reconstituted Tcrbd −/− mice then challenged with a C57BL/6 donor heart that expressed H-2K d as a transgene (B6.K d ; Honjo et al., 2004) while simultaneously receiving anti-CD154 mAb. We reasoned that only established H-2K d -specific memory CD4 T cells would be able to provide co-stimulation-independent help for development of anti-H-2K d alloantibody responses against the B6.K d graft (Conlon et al., 2012a).…”

Section: Resultsmentioning

confidence: 99%

“…Bm12.Kd.IE mice were created in house by first crossing bm12 × B6.Kd, selecting from the offspring those expressing I-A bm12 and H-2K d , but not I-A b (bm12.Kd), and then crossing them with ABOIE mice and selecting offspring expressing I-A bm12 , I-E, and H-2K d , but not I-A b . For TCR transgenic animals, Rag2 −/− TEa mice (H-2 b ; TEa), specific for I-A b -restricted I-E d 52-68 peptide, were gifted by Prof. A. Rudensky (University of Washington; Grubin et al., 1997); Rag1 −/− TCR75 mice (H-2 b ; TCR75), specific for I-A b -restricted H-2K d 54-68 peptide, were gifted by Prof. P. Bucy (University of Alabama; Honjo et al., 2004); Rag2 −/− ABM mice (H-2 b ; ABM), I-A bm12 restricted, were gifted by Dr. T. Crompton (Imperial College; Bäckström et al., 1998); and Rag1 −/− Marilyn mice (H-2 b ; Mar), specific for the I-A b -restricted H-Y dby 608–622 peptide, were gifted by Dr. Di Scott (Imperial College; Lantz et al., 2000). Mice were bred and maintained in specific-pathogen-free animal facilities, and all experiments were approved by the UK Home Office under the Animals (Scientific Procedures) Act 1986.…”

Section: Methodsmentioning

confidence: 99%

Diversity of the CD4 T Cell Alloresponse: The Short and the Long of It

et al. 2016

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SummaryMHC alloantigen is recognized by two pathways: “directly,” intact on donor cells, or “indirectly,” as self-restricted allopeptide. The duration of each pathway, and its relative contribution to allograft vasculopathy, remain unclear. Using a murine model of chronic allograft rejection, we report that direct-pathway CD4 T cell alloresponses, as well as indirect-pathway responses against MHC class II alloantigen, are curtailed by rapid elimination of donor hematopoietic antigen-presenting cells. In contrast, persistent presentation of epitope resulted in continual division and less-profound contraction of the class I allopeptide-specific CD4 T cell population, with approximately 10,000-fold more cells persisting than following acute allograft rejection. This expanded population nevertheless displayed sub-optimal anamnestic responses and was unable to provide co-stimulation-independent help for generating alloantibody. Indirect-pathway CD4 T cell responses are heterogeneous. Appreciation that responses against particular alloantigens dominate at late time points will likely inform development of strategies aimed at improving transplant outcomes.

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“…cells or T cells from TCR Tg mice (TCR75) with specificity for a single peptide derived from the H-2K d MHC class I molecule presented by the I-A b class II molecule (K d 54 -68 /I-A b ) on the C57BL/6 (B6) background [50]. APC and hearts were obtained from transgenic B6 mice expressing the genomic sequence of H-2K d (B6.K d ) [51], the chicken OVA gene (B6.OVA), or both (B6.K d .OVA) transgenes.…”

Section: Resurrection Of Cd8 ؉ Ts Cellsmentioning

confidence: 99%

CD8+ suppressor T cells resurrected

Kapp¹,

Bucy²

2008

Human Immunology

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Evidence for Cooperativity in the Rejection of Cardiac Grafts Mediated by CD4+ TCR Tg T Cells Specific for a Defined Allopeptide

Abstract: Understanding the mechanisms of rejection of organs transplanted between unrelated individuals is confounded by the complexity of the alloantigens and the diversity of T cells responding to these alloantigens. To circumvent these problems, we developed a transgenic (

Cited by 29 publications

References 26 publications

Transitional‐2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival

Transitional‐2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival

Diversity of the CD4 T Cell Alloresponse: The Short and the Long of It

CD8+ suppressor T cells resurrected

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