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ABSTRACT: Previous studies have indicated that blockade of signaling through the T-cell receptor (TCR)/calcineurin/nuclear factor of activated T cells (NFAT) pathway impairs transplantation tolerance induced with anti-CD154 antibody. By using an allogeneic bone marrow transplantation model, we examined the role of the TCR/calcineurin/NFAT pathway for tolerance induction with anti-CD154. Calcineurin blockade by cyclosporine A led to a failure of CD8 but not CD4 tolerance, and experiments in NFAT1(-/-) mice replicated this effect. Studies in thymectomized mice demonstrated that blockade of the calcineurin/NFAT pathway after bone marrow transplantation led to a failure of peripheral CD8 tolerance. Moreover, CD8 adoptive transfer studies demonstrated that NFAT1 is cell-intrinsically required for peripheral CD8 tolerance. NFAT1 deficiency did not impair CD8 T-cell up-regulation of PD1, which is required for CD8 tolerance in this model. NFAT1 has previously been shown to have a role in CD4 cells for anergy induction and for programming CD4 cells to become regulatory cells. By generating mice lacking NFAT1 in CD4 but not CD8 cells, we demonstrate that NFAT1 is neither required for CD4 tolerance induction nor for their regulatory function on CD8 T cells. Thus, our study reveals a CD8 T cell-intrinsic NFAT1 requirement for CD8 tolerance in vivo.
Blood 12/2009; 115(6):1280-7. · 9.90 Impact Factor
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ABSTRACT: Mixed chimerism and donor-specific tolerance are achieved in mice receiving 3 Gy of total body irradiation and anti-CD154 mAb followed by allogeneic bone marrow (BM) transplantation. In this model, recipient CD4 cells are critically important for CD8 tolerance. To evaluate the role of CD4 cells recognizing donor MHC class II directly, we used class II-deficient donor marrow and were not able to achieve chimerism unless recipient CD8 cells were depleted, indicating that directly alloreactive CD4 cells were necessary for CD8 tolerance. To identify the MHC class II(+) donor cells promoting this tolerance, we used donor BM lacking certain cell populations or used positively selected cell populations. Neither donor CD11c(+) dendritic cells, B cells, T cells, nor donor-derived IL-10 were critical for chimerism induction. Purified donor B cells induced early chimerism and donor-specific cell-mediated lympholysis tolerance in both strain combinations tested. In contrast, positively selected CD11b(+) monocytes/myeloid cells did not induce early chimerism in either strain combination. Donor cell preparations containing B cells were able to induce early deletion of donor-reactive TCR-transgenic 2C CD8 T cells, whereas those devoid of B cells had reduced activity. Thus, induction of stable mixed chimerism depends on the expression of MHC class II on the donor marrow, but no requisite donor cell lineage was identified. Donor BM-derived B cells induced early chimerism, donor-specific cell-mediated lympholysis tolerance, and deletion of donor-reactive CD8 T cells, whereas CD11b(+) cells did not. Thus, BM-derived B cells are potent tolerogenic APCs for alloreactive CD8 cells.
The Journal of Immunology 10/2008; 181(6):4371-80. · 5.79 Impact Factor
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ABSTRACT: Allogeneic bone marrow chimerism induces robust systemic tolerance to donor alloantigens. Achievement of chimerism requires avoidance of marrow rejection by pre-existing CD4 and CD8 T cells, either of which can reject fully MHC-mismatched marrow. Both barriers are overcome with a minimal regimen involving anti-CD154 and low dose (3 Gy) total body irradiation, allowing achievement of mixed chimerism and tolerance in mice. CD4 cells are required to prevent marrow rejection by CD8 cells via a novel pathway, wherein recipient CD4 cells interacting with recipient class II MHC tolerize directly alloreactive CD8 cells. We demonstrate a critical role for recipient MHC class II, B cells, and dendritic cells in a pathway culminating in deletional tolerance of peripheral alloreactive CD8 cells.
The Journal of Immunology 08/2008; 181(1):165-73. · 5.79 Impact Factor
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ABSTRACT: Although interaction between programmed death-1 (PD-1) and the ligand PD-L1 has been shown to mediate CD8 cell exhaustion in the setting of chronic infection or the absence of CD4 help, a role for this pathway in attenuating early alloreactive CD8 cell responses has not been identified. We demonstrate that the PD-1/PD-L1 pathway is needed to rapidly tolerize alloreactive CD8 cells in a model that requires CD4 cells and culminates in CD8 cell deletion. This protocol involves allogeneic bone marrow transplantation (BMT) following conditioning with low-dose total body irradiation and anti-CD154 antibody. Tolerized donor-reactive T-cell receptor transgenic CD8 cells are shown to be in an abortive activation state prior to their deletion, showing early and prolonged expression of activation markers (compared with rejecting CD8 cells) while being functionally silenced by day 4 after transplantation. Although both tolerized and rejecting alloreactive CD8 cells up-regulate PD-1, CD8 cell tolerance is dependent on the PD-1/PD-L1 pathway. In contrast, CD4 cells are tolerized independently of this pathway following BMT with anti-CD154. These studies demonstrate a dichotomy between the requirements for CD4 and CD8 tolerance and identify a role for PD-1 in the rapid tolerization of an alloreactive T-cell population via a deletional mechanism.
Blood 07/2008; 112(5):2149-55. · 9.90 Impact Factor
