CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance

Kurtz, Josef; Raval, Forum; Vallot, Casey; Der, Jayden; Sykes, Megan

doi:10.1182/blood-2008-01-133736

Cited by 34 publications

(23 citation statements)

References 78 publications

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“…Contrasting data on the expression of CD80 by MSC can further confirm MSC hypoimmunogenicity: in fact, CD80 may exert an inhibitory role on lymphocytes via CD152 (CTLA-4) binding, thus attenuating lymphocyte response [73,74]. Other authors suggested that this process may be enhanced in the absence of CD86, which binds CD28: CD86 blockade, in presence of intact CD80, results in alloantigen-specific tolerance [75,76].…”

Section: Recent Data On the Expression Of Relevant Immunomodulatory Mmentioning

confidence: 90%

Novel Immunomodulatory Markers Expressed by Human WJ-MSC: an Updated Review in Regenerative and Reparative Medicine

Rocca¹,

Corrao

Iacono

et al. 2012

TOTERMJ

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Mesenchymal (stromal) stem cells (MSC) are a broad class of stromal populations which are able to differentiate towards mature cell types, and do express molecules involved in immune modulation, tolerance induction and inflammation dampening. MSC can be virtually isolated from each adult organ, as well as from foetus-associated perinatal tissues. In particular, Wharton's jelly-derived MSC (WJ-MSC) bear all of these key properties, together with their ease of sourcing and lack of ethical issues.Cellular therapy is a key technique in regenerative medicine approaches, in particular for the treatment of diseases in which physiological processes of cellular repopulation are blocked by the underlying pathological conditions. Recent data enlightened the ability of administered cells to act also in a repopulation-independent fashion in target organs, since their peculiar immunomodulatory and anti-inflammatory features may favor organ self-repair by reactivating local progenitors by both cell-mediated or paracrine mechanisms. Translating classical regenerative medicine to "reparative medicine" or "support medicine" should represent a further therapeutic strategy independent from the differentiation capacity of MSC populations.Recent data further highlighted that WJ-MSC outperform BM-MSC (which are now being applied clinically) both in terms of immune modulation and lack of tumorigenesis (or tumor-promoting activities) in vivo. Starting from these premises, this paper analyzes the recent data on the biology of WJ-MSC, considering the role of both naïve and differentiated cells in immune modulation. In particular, the role of tolerance promoting pathways via non-classical B7 costimulators or class Ib MHC molecules are examined. In addition, we also analyzed the interconnections with other mechanicistic pathways (as those driven by matrix degrading metalloproteinases) in immune modulation. Our observations strongly support the notion that WJ-MSC may constitute a new tool in regenerative and reparative medicine applications.

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Section: Recent Data On the Expression Of Relevant Immunomodulatory Mmentioning

confidence: 90%

Novel Immunomodulatory Markers Expressed by Human WJ-MSC: an Updated Review in Regenerative and Reparative Medicine

Rocca¹,

Corrao

Iacono

et al. 2012

TOTERMJ

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“…Of these 4 pathways, 3 (LAG-3, PD-1, and TGF-␤) are not required for CD4 T-cell tolerance, highlighting the disparate mechanisms involved in tolerizing the 2 T-cell subsets in the same mice, despite the common end point of deletion of peripheral donor-specific CD4 13 and CD8 9 T cells. Both CD4 34 and CD8 T-cell subsets (Figure 4) require the CTLA4/B7.1/B7.2 pathway cell-intrinsically to be tolerized. Together with previously published data demonstrating a requisite role for the NFAT1 transcription factor 31 in CD8 but not CD4 T-cell tolerance, these data will promote the development of approaches to using pathway-specific immune therapies for tolerance induction.…”

Section: Discussionmentioning

confidence: 99%

“…34 Because CD8 T cells depend on CD4 T cells for tolerance induction in this model, it would not be informative to use anti-CTLA4 mAb to assess the requirement For personal use only. on May 12, 2018. by guest www.bloodjournal.org From for CTLA4 on CD8 T cells.…”

Section: The Ctla4 and Pd-1 Pathways Are Required Cd8 T-cell Intrinsimentioning

confidence: 99%

“…34 Because CD8 T cells depend on CD4 T cells for tolerance induction in this model, it would not be informative to use anti-CTLA4 mAb to assess the requirement Figure 4A, CTLA4/B7.1/B7.2-deficient CD8 T cells promptly rejected donor BM, indicating that this pathway is required on CD8 T cells to achieve tolerance.…”

Section: The Ctla4 and Pd-1 Pathways Are Required Cd8 T-cell Intrinsimentioning

confidence: 99%

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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

Self Cite

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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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“…Antigen transport to the cell surface coincides with increased expression of costimulatory molecules, such as B7-1/CD80, B7-2/ CD86, and major histocompatibility complexes (19), and as such, their expression is increased in NLGP-cultured DCs, including both healthy and CaCx DCs. CD40-CD40L interaction plays a critical role in DC-T cell cross talk (24) and NLGP-upregulated CD40 expression on CaCx DC surfaces (Fig.…”

Section: Resultsmentioning

confidence: 99%

Neem Leaf Glycoprotein Partially Rectifies Suppressed Dendritic Cell Functions and Associated T Cell Efficacy in Patients with Stage IIIB Cervical Cancer

Roy¹,

Goswami²,

Bose³

et al. 2011

Clin. Vaccine Immunol.

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Myeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients. In vitro NLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGPmatured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC-based immune functions is noted in vitro at a fairly advanced stage of CaCx, and thus, further exploration of ex vivo and in vivo DC-based vaccines is proposed. Moreover, the DC maturating efficacy of NLGP might be much more effective in the earlier stages of CaCx, where the extent of immune dysregulation is less and, thus, the scope of further investigation may be explored.Cervical cancer (CaCx) is the second most common type of tumor worldwide, and its incidence is disproportionately high (Ͼ80%) in the developing world (35). It remains an important health problem for women, especially in underserved and socioeconomically backward classes (29). Immunotherapy with mature monocyte-derived dendritic cells (DCs) pulsed with human papillomavirus type 16 or 18 (HPV16/18) E7 oncoprotein antigens is a promising approach in treating this disease (32). These alternate therapeutic approaches are aimed toward controlling late-stage detection and preventing recurrence (31), an arena where application of traditional therapeutic approaches like radical surgery or radiotherapy is difficult. DCs are extremely potent antigen-presenting cells (APC) that function in vitro and in vivo to initiate T lymphocyte responses to antigens (14). The ability of DCs to stimulate T cells is attributed to their dichotomous nature as immature DCs (iDCs) and mature DCs (mDCs) (30). Immature DCs effectively capture antigens but lack full T cell stimulatory activity and are sensitive to the immunosuppressive effects of an immunoregulatory cytokine, interleukin-10 (IL-10). In contrast, mature DCs exhibit an enhanced level of antigen presentation, full T cell stimulatory activity, production of a type 1 cytokine, IL-12, and low production of a type 2 cytokine, IL-10 (36).In the last few years, a multitude of diagnostic studies have shown a strong immunosuppressive state of the cervical epithelium, which is one major reason for the fragile health of cervical cancer patient...

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CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance

Cited by 34 publications

References 78 publications

Novel Immunomodulatory Markers Expressed by Human WJ-MSC: an Updated Review in Regenerative and Reparative Medicine

Novel Immunomodulatory Markers Expressed by Human WJ-MSC: an Updated Review in Regenerative and Reparative Medicine

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

Neem Leaf Glycoprotein Partially Rectifies Suppressed Dendritic Cell Functions and Associated T Cell Efficacy in Patients with Stage IIIB Cervical Cancer

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