Ablation of interferon regulatory factor 4 in T cells induces “memory” of transplant tolerance that is irreversible by immune checkpoint blockade

Zhang, Hedong; Wu, Jie; Zou, Dawei; Xiang, Xiao; Yan, Hui; Li, Xian Chang; Chen, Wenhao

doi:10.1111/ajt.15196

Cited by 22 publications

(24 citation statements)

References 31 publications

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“…Another setting of return to tolerance was described in self-antigen-specific CD8 + T cells following transient activation by homeostatic proliferation in lymphopenic hosts and was also ascribed to epigenetic imprinting (38). In transplantation, a T cell-restricted deficiency in IRF4 was recently reported to result in spontaneous donor-specific tolerance of cardiac allografts associated with impaired memory development and hyporesponsiveness of alloreactive CD4 + T cells, even if the animals received anti-PD1 and anti-CTLA-4 at the time of initial cardiac transplantation, which prevented graft acceptance (39,40). A similar phenomenon of return of tolerance may have been observed in kidney allograft recipient monkeys in which tolerance was induced by a regimen resulting in transient mixed chimerism, as injections of IL-2 resulted in rapid rejection of previously tolerated allografts, but cessation of IL-2 aborted the rejection process and restored kidney function (41).…”

Section: Discussionmentioning

confidence: 99%

Resilience of T cell-intrinsic dysfunction in transplantation tolerance

Miller

McIntosh

Wang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Following antigen stimulation, naïve T cells differentiate into memory cells that mediate antigen clearance more efficiently upon repeat encounter. Donor-specific tolerance can be achieved in a subset of transplant recipients, but some of these grafts are rejected after years of stability, often following infections. Whether T cell memory can develop from a tolerant state and whether these formerly tolerant patients develop antidonor memory is not known. Using a mouse model of cardiac transplantation in which donor-specific tolerance is induced with costimulation blockade (CoB) plus donor-specific transfusion (DST), we have previously shown that systemic infection with Listeria monocytogenes (Lm) months after transplantation can erode or transiently abrogate established tolerance. In this study, we tracked donor-reactive T cells to investigate whether memory can be induced when alloreactive T cells are activated in the setting of tolerance. We show alloreactive T cells persist after induction of cardiac transplantation tolerance, but fail to acquire a memory phenotype despite becoming antigen experienced. Instead, donor-reactive T cells develop T cell-intrinsic dysfunction evidenced when removed from the tolerant environment. Notably, Lm infection after tolerance did not rescue alloreactive T cell memory differentiation or functionality. CoB and antigen persistence were sufficient together but not separately to achieve alloreactive T cell dysfunction, and conventional immunosuppression could substitute for CoB. Antigen persistence was required, as early but not late surgical allograft removal precluded the acquisition of T cell dysfunction. Our results demonstrate transplant tolerance-associated T cell-intrinsic dysfunction that is resistant to memory development even after Lm-mediated disruption of tolerance.

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Section: Discussionmentioning

confidence: 99%

Resilience of T cell-intrinsic dysfunction in transplantation tolerance

Miller

McIntosh

Wang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…They are essential for preventing autoimmunity and maintaining immune homeostasis and also play a key role in inducing T cell dysfunction that contributes to tumor immune escape, chronic persistent viral infection, and transplant tolerance 3 - 5 . Our recent study found that enhancing PD-1 expression in T cells by ablating the transcription factor, interferon regulatory factor 4 (IRF4), or inhibiting the MEK1/2 pathway led to T cell dysfunction and induced transplant tolerance in mice 6 , 7 . However, whether enhancing CTLA-4 expression of alloreactive T cells can prevent transplant rejection remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation

Cui¹,

Yu²,

Xu³

et al. 2020

Theranostics

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Background : The immune checkpoint cytotoxic T lymphocyte antigen-4 (CTLA-4), induced upon T cell activation but degraded quickly, has been targeted in the clinical therapy of advanced cancers and autoimmune diseases. However, whether inhibiting CTLA-4 degradation ameliorates transplant rejection remains unknown. Methods : The CTLA-4 expression in activated murine T cells treated with the inhibitors mediating protein degradation was detected by flow cytometry (FCM). CD45.1 mice, which received TEa T cells and underwent heart transplantation, were administrated with the inhibitor. Subsequently, CTLA-4 expression of TEa T cells was analyzed. Murine skin and heart transplantation models were built, then the survival and histopathology of the allografts, and T cell subsets in the spleens of each group were compared. Results : Chloroquine (CQ) was identified as an inhibitor of CTLA-4 degradation, which augmented both surface and total CTLA-4 expression in T cells. It considerably prolonged the skin and heart allograft survival time and reduced the infiltration of inflammatory cells in allografts. Besides decreasing the frequencies of the CD4 + and CD8 + effector T cells, especially IFN-γ producing T cells, CQ also increased the proportion of regulatory T cells in the spleen. The CTLA-4 blockade abrogated the benefits of CQ on the survival of heart allografts. Moreover, CQ enhanced CTLA-4 expression in activated human T cells and reduced the secretion of IFN-γ in human mixed lymphocyte reaction. Conclusion : Targeting CTLA-4 degradation provides a novel means to prevent transplant rejection and induce transplant tolerance.

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“…It remains unclear whether T cell exhaustion naturally occurs in response to transplant 10 . We found that IRF4 deletion leads to transplant tolerance by inducing an exhaustion‐like phenotype of T cells, evident by their high PD‐1 expression and impaired cytokine production 11,12 . Miller et al 13 demonstrated that CD154 blockade plus donor‐specific transfusion, an experimental approach to transplant tolerance, also induces a PD‐1 hi phenotype of alloreactive T cells.…”

Section: Introductionmentioning

confidence: 76%

“…We demonstrated previously that transplant of Balb/c hearts (larger than the skin grafts) into B6 mice effectively activated both endogenous alloreactive T cells and the transferred TEa cells and did not induce T cell exhaustion/dysfunction. Indeed, we had to delete a transcription factor IRF4 to induce T cell dysfunction and transplant tolerance 11,12 . Interestingly, dramatically increasing graft size (eg, transplant of 2 kidneys plus 2 hearts in 1 recipient) or reducing alloreactive T cell frequency promotes the acceptance of MHC‐mismatched grafts 20,21 .…”

Section: Discussionmentioning

confidence: 99%

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T cell exhaustion is associated with antigen abundance and promotes transplant acceptance

Zou

Dai

Zhang

et al. 2020

American Journal of Transplantation

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Exhaustion of T cells limits their ability to clear chronic infections or eradicate tumors. Here, in the context of transplant, we investigated whether T cell exhaustion occurs and has a role in determining transplant outcome. A peptide/MHC tetramer‐based approach was used to track exhausted CD8+ T cells in a male‐to‐female skin transplant model. Transplant of large whole‐tail skins, but not small tail skins (0.8 cm × 0.8 cm), led to exhaustion of anti‐male tetramer+ CD8+ T cells and subsequently the acceptance of skin grafts. To study CD4+ T cell exhaustion, we used the TCR‐transgenic B6 TEa cells that recognize a major transplant antigen I‐Eα from Balb/c mice. TEa cells were adoptively transferred either into B6 recipients that received Balb/c donor skins or into CB6F1 mice that contained an excessive amount of I‐Eα antigen. Adoptively transferred TEa cells in skin‐graft recipients were not exhausted. By contrast, virtually all adoptively transferred TEa cells were exhausted in CB6F1 mice. Those exhausted TEa cells lost ability to reject Balb/c skins upon further transfer into lymphopenic B6.Rag1−/− mice. Hence, T cell exhaustion develops in the presence of abundant antigen and promotes transplant acceptance. These findings are essential for better understanding the nature of transplant tolerance.

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Ablation of interferon regulatory factor 4 in T cells induces “memory” of transplant tolerance that is irreversible by immune checkpoint blockade

Cited by 22 publications

References 31 publications

Resilience of T cell-intrinsic dysfunction in transplantation tolerance

Resilience of T cell-intrinsic dysfunction in transplantation tolerance

Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation

T cell exhaustion is associated with antigen abundance and promotes transplant acceptance

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