Exhaustive Differentiation of Alloreactive CD8+ T Cells: Critical for Determination of Graft Acceptance or Rejection

Steger, Ulrich; Denecke, Christian; Sawitzki, Birgit; Karim, Mahzuz; Jones, Nick D.; Wood, Kathryn J.

doi:10.1097/tp.0b013e31816dd64a

Cited by 49 publications

(47 citation statements)

References 45 publications

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“…The potential antiapoptotic action of B7-H4 on islet cells raises the potential malignant transformation induced by ectopic overexpression of B7-H4. B7-H4 has been observed to be overexpressed in various cancers, such as breast, ovarian, and pancreatic cancers, suggesting that B7-H4 overexpression might associate with epithelial cell transformation (39,40). So, although B7-H4 gene transfer may on one hand enhance ␤-cell survival, it may also result in transformation (e.g.…”

Section: Discussionmentioning

confidence: 98%

Local Expression of B7-H4 by Recombinant Adenovirus Transduction in Mouse Islets Prolongs Allograft Survival

et al. 2009

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Section: Discussionmentioning

confidence: 98%

Local Expression of B7-H4 by Recombinant Adenovirus Transduction in Mouse Islets Prolongs Allograft Survival

et al. 2009

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“…Several groups have reported on the impact of alloantigen load on alloreactive CD8+ T cells and demonstrated evidence of T cell exhaustion with decreased proliferative capacity and reduced effector cytokine production (Quezada et al, 2003; Steger et al, 2008). However, the expression of coinhibitory molecules was not examined in these studies.…”

Section: T Cell Exhaustion Negative Costimulation and Transplantationmentioning

confidence: 99%

The Role of Coinhibitory Signaling Pathways in Transplantation and Tolerance

McGrath¹,

Najafian²

2012

Front. Immun.

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Negative costimulatory molecules, acting through so-called inhibitory pathways, play a crucial role in the control of T cell responses. This negative “second signal” opposes T cell receptor activation and leads to downregulation of T cell proliferation and promotes antigen specific tolerance. Much interest has focused upon these pathways in recent years as a method to control detrimental alloresponses and promote allograft tolerance. However, recent experimental data highlights the complexity of negative costimulatory pathways in alloimmunity. Varying effects are observed from molecules expressed on donor and recipient tissues and also depending upon the activation status of immune cells involved. There appears to be significant overlap and redundancy within these systems, rendering this a challenging area to understand and exploit therapeutically. In this article, we will review the literature at the current time regarding the major negative costimulation pathways including CTLA-4:B7, PD-1:PD-L1/PD-L2 and PD-L1:B7-1, B7-H3, B7-H4, HVEM:BTLA/CD160, and TIM-3:Galectin-9. We aim to outline the role of these pathways in alloimmunity and discuss their potential applications for tolerance induction in transplantation.

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“…In the case of transplantation, the relationship between the mass of donor tissue transplanted and rejection or acceptance has previously been demonstrated in a study [43] showing that simultaneous transplantation of two kidneys and two hearts resulted in long-term graft acceptance, whereas single allogeneic heart and kidney graft were rejected acutely. Another study [35 ▪▪ ] extended these observations and demonstrated that CD8 + T-cell exhaustion followed by deletion of the alloreactive T-cell repertoire was responsible for prolonged liver allograft survival compared with smaller-sized heart and kidney transplantation. Similarly, utilizing islet, skin and heart transplant models, it was demonstrated that a threshold T-cell frequency is required to mediate rejection [44], that a low ratio of T-cell frequency to donor tissue mass is a critical determinant of donor-specific hyporesponsiveness and graft survival [45] and that low- frequency donor-specific T-cell responses are regulated by the PD-1 pathway [46].…”

Section: Factors Affecting T-cell Exhaustionmentioning

confidence: 98%

“…A more direct evidence of T-cell exhaustion in transplantation was provided by an elegant study [35 ▪▪ ] that demonstrated that a rapid and extensive activation and proliferation of the donor-reactive CD8 + T cells in the initial period after liver transplantation was followed by CD8 + T-cell exhaustion characterized by unresponsiveness and deletion of the alloreactive T-cell repertoire. The most direct evidence for T-cell exhaustion in transplantation was provided recently in a model of chronic allograft rejection [36 ▪ ] in which fucosyltransferase-VII–deficient ( Fut7 −/− ) recipients, with impaired selectin-dependent leukocyte recruitment, exhibited long-term graft survival with minimal vasculopathy compared with wild-type controls.…”

Section: Evidence For T-cell Exhaustion In Transplantationmentioning

confidence: 99%

T-cell exhaustion in allograft rejection and tolerance

Thorp

Stehlik

Ansari³

2015

Current Opinion in Organ Transplantation

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Purpose of review The role of T-cell exhaustion in the failure of clearance of viral infections and tumors is well established. There are several ongoing trials to reverse T-cell exhaustion for treatment of chronic viral infections and tumors. The mechanisms leading to T-cell exhaustion and its role in transplantation, however, are only beginning to be appreciated and are the focus of the present review. Recent findings Exhausted T cells exhibit a distinct molecular profile reflecting combinatorial mechanisms involving the interaction of multiple transcription factors important in control of cell metabolism, acquisition of effector function and memory capacity. Change of microenvironmental cues and limiting leukocyte recruitment can modulate T-cell exhaustion. Impaired leukocyte recruitment induces T-cell exhaustion and prevents allograft rejection. Summary Preventing or reversing T-cell exhaustion may lead to prevention of transplant tolerance or triggering of rejection; therefore, caution should be exercised in the use of agents blocking inhibitory receptors for the treatment of chronic viral infections or tumors in transplant recipients. Further definition of the role of T-cell exhaustion in clinical transplantation and an understanding of the mechanisms of induction of T-cell exhaustion are needed to develop strategies for preventing allograft rejection and induction of tolerance.

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Exhaustive Differentiation of Alloreactive CD8+ T Cells: Critical for Determination of Graft Acceptance or Rejection

Abstract: The rapid and extensive initial activation and differentiation of donor-reactive CD8+ T cells that occurs after liver transplantation leads to clonal exhaustion or deletion of the alloreactive CD8+ T-cell repertoire resulting in spontaneous tolerance induction.

Cited by 49 publications

References 45 publications

Local Expression of B7-H4 by Recombinant Adenovirus Transduction in Mouse Islets Prolongs Allograft Survival

Local Expression of B7-H4 by Recombinant Adenovirus Transduction in Mouse Islets Prolongs Allograft Survival

The Role of Coinhibitory Signaling Pathways in Transplantation and Tolerance

T-cell exhaustion in allograft rejection and tolerance

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