Striking Dichotomy of PD-L1 and PD-L2 Pathways in Regulating Alloreactive CD4+ and CD8+ T Cells In Vivo

Habicht, Antje; Kewalaramani, R; Vu, Minh Diem; Demirci, G.; Blazar, Bruce R.; Sayegh, Mohamed H.; Li, Xian Chang

doi:10.1111/j.1600-6143.2007.01999.x

Cited by 50 publications

(31 citation statements)

References 31 publications

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“…A dichotomy between the effects of PD-L1 and PD-L2 was previously described in a GVH model, but only PD-L2 and not PD-L1 was found to affect CD8 cell expansion. 44 In contrast to our demonstration that PD-L1 was not involved in the tolerization of CD4 T cells ( 8 and Figure 5A), only PD-L1 and not PD-L2 was found to inhibit CD4-dependent skin allograft rejection. 45 In a model of cardiac allograft acceptance induced with CTLA4-Ig, recipient and donor PD-L1, but not PD-L2, was required to achieve graft acceptance.…”

Section: Discussioncontrasting

confidence: 54%

LAG-3, TGF-β, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L

Lucas

Workman

Beyaz

et al. 2011

Blood

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Administration of a single dose of anti-CD40L mAb at the time of allogeneic BM transplantation tolerizes peripheral alloreactive T cells and permits establishment of mixed hematopoietic chimerism in mice. Once engrafted, mixed chimeras are systemically tolerant to donor Ags through a central deletion mechanism and will accept any donor organ indefinitely. We previously found that the PD-1/ PD-L1 pathway is required for CD8 T-cell tolerance in this model. However, the cell population that must express PD-1 and the role of other inhibitory molecules were unknown. Here, we report that LAG-3 is required for long-term peripheral CD8 but not CD4 T-cell tolerance and that this requirement is CD8 cell-extrinsic. In contrast, adoptive transfer studies revealed a CD8 T cell-intrinsic requirement for CTLA4/B7.1/B7.2 and for PD-1 for CD8 T-cell tolerance induction. We also observed that both PD-L1 and PD-L2 are independently required on donor cells to achieve T-cell tolerance. Finally, we uncovered a requirement for TGF-␤ signaling into T cells to achieve peripheral CD8 but not CD4 T-cell tolerance in this in vivo system. (Blood. 2011;117(20):5532-5540) IntroductionA long-standing goal of immunologists has been to develop ways of controlling the robust immunologic response against allogeneic Ags to prevent destruction of tissue allografts while maintaining the ability to protect from pathogens. An effective approach to inducing solid organ transplantation tolerance involves establishment of mixed hematopoietic chimerism, a state in which both recipient and donor BM cells coexist in one individual. 1,2 Dual hematopoiesis from both recipient and donor hematopoietic stem cells ensures that the recipient's thymus is seeded with APCs from both sources. Any newly developing T cells with strong TCR reactivity to either host or donor Ags will be negatively selected on these APCs in the thymus, thereby conferring lifelong, systemic, donor-specific tolerance in mixed chimeras. 3 Clinically a protocol using combined BM and organ graft transplantation has necessitated extensive T-cell depletion and thymic irradiation of the recipient to overcome the barrier posed by preexisting alloreactive T cells. 4 This nonselective T-cell ablation leaves the patient immunocompromised for a period of time. Thus, we are using a mouse BM transplantation (BMT) model to develop and dissect mechanisms of peripheral T-cell tolerance for induction of mixed chimerism using approaches that avoid lymphoablation of the recipient.One of the most effective experimental approaches to tolerance induction involves blockade of the CD40:CD40L pathway, [5][6][7] which reduces expression of costimulatory ligands and inflammatory cytokines by APCs. When blocking anti-CD40L is given together with allogeneic BMT, preexisting donor-reactive T cells in the periphery are rapidly rendered unresponsive 8 and specifically deleted. 1,2,9 Unfortunately, use of anti-CD40L in nonhuman primates and humans has been associated with thromboembolic complications. 10 The studies describe...

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Section: Discussioncontrasting

confidence: 54%

LAG-3, TGF-β, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L

Lucas

Workman

Beyaz

et al. 2011

Blood

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“…Whereas a recent study reports that blocking PD-L2 was predominant in limiting alloreactive CD8 ϩ CD28KO T-cell proliferation, 29 blockade of PD-L1 but not PD-L2 abrogated tolerance induced by CTLA-4.Ig treatment in a fully allogeneic heart transplant model and induced expansion of effector CD8 T cells in another study. 30 In another model, PD-L1 was shown to be involved in the deletion of activated CD8 T cells specifically in the liver.…”

Section: Discussionmentioning

confidence: 84%

Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway

Haspot

Fehr

Gibbons

et al. 2008

Blood

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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

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“…Alefacept treatment led to an increased amount of PDL1 expressing APCs (CD19 ϩ B cells) and CD4 ϩ T cells compared with activated but untreated cells. PDL1 negatively regulates T cell activation, promotes T cell apoptosis and has been reported to play an important role in transplantation tolerance (23)(24)(25)(26)(27)(28). How Alefacept induces PDL1 expression on B cells needs to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…These gene markers were selected for the following reasons: CD3 as a control to follow potential changes in T cell composition at transcriptional level, CD69 as Haider et al (15) showed that nonresponders express higher transcription levels of CD69 in pretreatment PBMCs, Foxp3 to indirectly study changes in regulatory T cell frequencies, PD-L1 to asses differences in gene expression of negatively regulating costimulatory molecules (23)(24)(25)(26)(27)(28), and TOAG-1 (Acc. No: BE115945) and RHAMM as they have been recently described to be differentially expressed in the periphery during induction and maintenance of immunological tolerance in allogeneic kidney graft recipients (29).…”

Section: Discussionmentioning

confidence: 99%

Expression of Tolerance Associated Gene-1, a Mitochondrial Protein Inhibiting T Cell Activation, Can Be Used to Predict Response to Immune Modulating Therapies

Keeren

Friedrich

Gebuhr

et al. 2009

The Journal of Immunology

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Immune modulating therapies gain increasing importance in treatment of patients with autoimmune diseases such as psoriasis. None of the currently applied biologics achieves significant clinical improvement in all treated patients. Because the therapy with biologics is cost intensive and sometimes associated with side effects, noninvasive diagnostic tools for early prediction of responders are of major interest. We studied the effects of Alefacept (LFA3Ig), an approved drug for treatment of psoriasis, on leukocytes in vitro and in vivo to identify gene markers predictive for treatment response and to further investigate its molecular mechanisms of action. In an open-label study, 20 psoriasis patients were treated weekly with 15 mg Alefacept over 12 wk. We demonstrate that transcription of the tolerance-associated gene (TOAG-1) is significantly up-regulated whereas receptor for hyaluronic acid mediated migration (RHAMM) transcription is down-regulated in PBMCs of responding patients before clinical improvement. TOAG-1 is exclusively localized within mitochondria. Overexpression of TOAG-1 in murine T cells leads to increased susceptibility to apoptosis. Addition of Alefacept to stimulated human T cells in vitro resulted in reduced frequencies of activated CD137+ cells, increased TOAG-1 but reduced RHAMM expression. This was accompanied by reduced proliferation and enhanced apoptosis. Inhibition of proliferation was dependent on enhanced PDL1 expression of APCs. Thus, peripheral changes of TOAG-1 and RHAMM expression can be used to predict clinical response to Alefacept treatment in psoriasis patients. In the presence of APCs Alefacept can inhibit T cell activation and survival by increasing expression of TOAG-1 on T cells and PDL1 on APCs.

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Striking Dichotomy of PD-L1 and PD-L2 Pathways in Regulating Alloreactive CD4+ and CD8+ T Cells In Vivo

Cited by 50 publications

References 31 publications

LAG-3, TGF-β, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L

LAG-3, TGF-β, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L

Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway

Expression of Tolerance Associated Gene-1, a Mitochondrial Protein Inhibiting T Cell Activation, Can Be Used to Predict Response to Immune Modulating Therapies

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