PIRs mediate innate myeloid cell memory to nonself MHC molecules

Dai, Hehua; Lan, Peixiang; Zhao, Daqiang; Abou-Daya, Khodor I.; Liu, Wentao; Chen, Wen‐Hao; Friday, Andrew J.; Williams, Amanda L.; Sun, Tao; Chen, Jianjiao; Chen, Wei; Mortin-Toth, Steven M.; Danska, Jayne S.; Wiebe, Chris; Nickerson, Peter; Li, Tengfang; Mathews, Lisa; Turnquist, Hēth; Nicotra, Matthew L.; Gingras, Sébastien; Takayama, Eiji; Kubagawa, Hiromi; Shlomchik, Mark J.; Oberbarnscheidt, Martin H.; Li, Xian Chang; Lakkis, Fadi G.

doi:10.1126/science.aax4040

Cited by 112 publications

(109 citation statements)

References 28 publications

(25 reference statements)

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“…As to the mechanisms by which monocytes acquire allospecific memory, the PIR molecules were preferentially expressed on Ly6Chi monocytes, which significantly expanded after allogeneic antigen exposure. Specific memory independent of lymphoid cells can be transferred to an unimmunized recipient by transferring sorted Ly6Chi monocytes expanded from an immunized recipient, suggesting that clonal expansion of monocytes that express the particular PIR-A molecule that recognizes the particular MHC-I molecule in the immunogen underlies memory (51). This resembles the mechanism established in the case of allospecific NK cell memory (34).…”

Section: Allospecific Memory In Innate Immune Cells: Recognition Of Mmentioning

confidence: 88%

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Innate Allorecognition and Memory in Transplantation

et al. 2020

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Over the past few decades, we have witnessed a decline in the rates of acute rejection without significant improvement in chronic rejection. Current treatment strategies principally target the adaptive immune response and not the innate response. Therefore, better understanding of innate immunity in transplantation and how to target it is highly desirable. Here, we review the latest advances in innate immunity in transplantation focusing on the roles and mechanisms of innate allorecognition and memory in myeloid cells. These novel concepts could explain why alloimmune response do not abate over time and shed light on new molecular pathways that can be interrupted to prevent or treat chronic rejection.

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Section: Allospecific Memory In Innate Immune Cells: Recognition Of Mmentioning

confidence: 88%

“…In the third set of experiments (51,61), innate allorecognition and memory molecular pathways were interrupted. We observed that mouse renal allografts transplanted to recipients that lack either CD47 or PIR-A develop significantly less manifestations of chronic rejection.…”

Section: Role Of Innate Allorecognition In Rejectionmentioning

confidence: 99%

Innate Allorecognition and Memory in Transplantation

et al. 2020

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“…More recently, the Lakkis laboratory also demonstrated that polymorphisms in the SIRPa gene were required to induce monocyte memory is against non-self MHC molecules. In this study, it was demonstrated that deleting the PIR-A in the recipient or blocking the paired immunoglobulin-like receptor-A (PIR-A) binding to donor MHC-I with a PIR-A3/Fc inhibits alloantigen specific memory of myeloid cells and promotes indefinite allograft survival in a murine kidney and heart transplant model (142). Overall, these studies provide compelling evidence demonstrating that monocytes initiate the immune response, determine the critical role of SIRPa polymorphic differences in the activation of graft reactive macrophages and that the immunological memory to innate myeloid cells can be potentially targeted to promote the induction of transplantation tolerance.…”

Section: Macrophages and Rejectionmentioning

confidence: 99%

Macrophages in Organ Transplantation

et al. 2020

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Current immunosuppressive therapy has led to excellent short-term survival rates in organ transplantation. However, long-term graft survival rates are suboptimal, and a vast number of allografts are gradually lost in the clinic. An increasing number of animal and clinical studies have demonstrated that monocytes and macrophages play a pivotal role in graft rejection, as these mononuclear phagocytic cells recognize alloantigens and trigger an inflammatory cascade that activate the adaptive immune response. Moreover, recent studies suggest that monocytes acquire a feature of memory recall response that is associated with a potent immune response. This form of memory is called “trained immunity,” and it is retained by mechanisms of epigenetic and metabolic changes in innate immune cells after exposure to particular ligands, which have a direct impact in allograft rejection. In this review article, we highlight the role of monocytes and macrophages in organ transplantation and summarize therapeutic approaches to promote tolerance through manipulation of monocytes and macrophages. These strategies may open new therapeutic opportunities to increase long-term transplant survival rates in the clinic.

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“…Adaptive immunity focusing on T cell biology has dominated studies of transplant rejection in the past several decades. However, innate immunity has recently become recognized as an important player in transplantation ( 1 – 4 ), demonstrating previously unidentified roles in promoting ischemic reperfusion injuries ( 5 ), priming adaptive immune responses ( 1 , 6 ), or perpetuating chronic rejection ( 7 ). Among innate immune cells, tissue macrophages have been shown to influence organ homeostasis and defense ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Single cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection

Dangi¹,

Natesh²,

Husain³

et al. 2020

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Myeloid cells are increasingly recognized as major players in transplant rejection. Here, we used a murine kidney transplantation model and single cell transcriptomics to dissect the contribution of myeloid cell subsets and their potential signaling pathways to kidney transplant rejection. Using a variety of bioinformatic techniques, including machine learning, we demonstrate that kidney allograft–infiltrating myeloid cells followed a trajectory of differentiation from monocytes to proinflammatory macrophages, and they exhibited distinct interactions with kidney allograft parenchymal cells. While this process correlated with a unique pattern of myeloid cell transcripts, a top gene identified was Axl , a member of the receptor tyrosine kinase family Tyro3/Axl/Mertk (TAM). Using kidney transplant recipients with Axl gene deficiency, we further demonstrate that Axl augmented intragraft differentiation of proinflammatory macrophages, likely via its effect on the transcription factor Cebpb. This, in turn, promoted intragraft recruitment, differentiation, and proliferation of donor-specific T cells, and it enhanced early allograft inflammation evidenced by histology. We conclude that myeloid cell Axl expression identified by single cell transcriptomics of kidney allografts in our study plays a major role in promoting intragraft myeloid cell and T cell differentiation, and it presents a potentially novel therapeutic target for controlling kidney allograft rejection and improving kidney allograft survival.

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PIRs mediate innate myeloid cell memory to nonself MHC molecules

Cited by 112 publications

References 28 publications

Innate Allorecognition and Memory in Transplantation

Innate Allorecognition and Memory in Transplantation

Macrophages in Organ Transplantation

Single cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection

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