HLA‐G dimer targets Granzyme B pathway to prolong human renal allograft survival

Ajith, Ashwin; Portik-Dobos, Vera; Nguyen-Lefebvre, Anh Thu; Callaway, Christine; Horuzsko, Daniel D.; Kapoor, Rajan; Zayas, Carlos; Maenaka, Katsumi; Mulloy, Laura L.; Horuzsko, Anatolij

doi:10.1096/fj.201802017r

Cited by 20 publications

(19 citation statements)

References 52 publications

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“…48,49 In experimental models and by cell culture experiments it was shown that application of soluble HLA-G dimers inhibits activation of CD8 + T cells and downregulates granzyme B expression by binding to ILT2. 59 Soluble HLA-G in a dimerized form inhibits T cell responses, which suggests that it directly triggers ILT2. 60 ILT2 may also prevent efficient T cell activation: it is thought that ILT2 modulates CD8 + T cell activation by blocking the binding of HLA class I to CD8.…”

Section: Does Pregnancy Failure Results From Maternal T Cells Attackmentioning

confidence: 99%

“…Decidual CD8 + EM T cells express significantly lower perforin and granzyme B levels compared with their peripheral blood counterparts 48,49 . In experimental models and by cell culture experiments it was shown that application of soluble HLA‐G dimers inhibits activation of CD8 + T cells and downregulates granzyme B expression by binding to ILT2 59 . Soluble HLA‐G in a dimerized form inhibits T cell responses, which suggests that it directly triggers ILT2 60 .…”

Section: Maternal T Cells and Myeloid Cells In The Placental Bedmentioning

confidence: 99%

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Got your mother in a whirl: The role of maternal T cells and myeloid cells in pregnancy

Eikmans

Zwan

Claas

et al. 2020

HLA

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Appropriate development of the placenta is required for healthy pregnancy to occur. After implantation of the fertilized blastocyst, fetal trophoblasts invade the endometrium and myometrium of the mother's uterus to establish placentation. In this process, fetal trophoblasts encounter maternal immune cells. In this review, we focus on the role of maternal T cells and myeloid cells (macrophages, dendritic cells) in pregnancy and their interaction with trophoblasts. To retain immunologic tolerization, trophoblasts evade immune recognition by T cells and produce factors that modulate their phenotype and function. On top of that, the local environment at the maternal‐fetal interface favors expansion of regulatory T cells. Macrophages and dendritic cells are essential in maintaining a healthy pregnancy. They produce soluble factors and act as antigen‐presenting cells, thereby interacting with T cells. Herein, M2 macrophages, immature dendritic cells, CD4+ Th2 cells, and regulatory T cells represent an axis that maintains a local immune tolerant environment. We consider outstanding issues concerning these cell types and their pathways, which need to be addressed in future investigations. Data from recent single‐cell sequencing experiments of the placental bed, to study heterogeneity of maternal immune cells and to predict cell‐cell interactions, are discussed. Novel ways for long‐term culturing of primary trophoblasts allow for cell‐cell interaction studies in a functional way. Future directions should include study of the functionality of currently known and newly identified decidual immune cell subsets in healthy and complicated pregnancies, and their interaction with and modulation by trophoblast cells.

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Section: Does Pregnancy Failure Results From Maternal T Cells Attackmentioning

confidence: 99%

Section: Maternal T Cells and Myeloid Cells In The Placental Bedmentioning

confidence: 99%

Got your mother in a whirl: The role of maternal T cells and myeloid cells in pregnancy

Eikmans

Zwan

Claas

et al. 2020

HLA

View full text Add to dashboard Cite

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“…In addition, being an in vivo model, we avoided artificial culture conditions and growth factors essential for in vitro assays, allowing for a more dynamic and natural background for an allogeneic immune response. The NSG mouse used in this model has defective VDJ recombination and a mutation in the IL-2R gamma chain, allowing for maximal engraftment of human immune cells and making it the most amenable strain for studying allogeneic immune responses (20,(60)(61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

Humanized Mouse Model as a Novel Approach in the Assessment of Human Allogeneic Responses in Organ Transplantation

et al. 2021

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The outcome of organ transplantation is largely dictated by selection of a well-matched donor, which results in less chance of graft rejection. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching diminishes outcomes after solid organ transplantation. The current evaluation of HLA incompatibility does not provide information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a new method for analysis of alloimmune responsiveness between donor and recipient in vivo by introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient’s personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing provided a better recipient-donor match for one donor among two related donors. In contrast, assessment of an allogeneic response by mixed lymphocyte reaction (MLR) was indistinguishable between these donors. We determined that, in the recipient’s humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with markedly increased allograft rejection markers, including activated cytotoxic Granzyme B-expressing CD8+ T cells. Moreover, the same donor induced stronger upregulation of genes involved in the allograft rejection pathway as determined by transcriptome analysis of isolated human CD45+cells. Thus, the humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in organ transplantation. In addition, this approach could be used to evaluate the level of alloresponse in allogeneic cell-based therapies that include cell products derived from pluripotent embryonic stem cells or adult stem cells, both undifferentiated and differentiated, all of which will produce allogeneic immune responses.

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“…In a cohort of 81 healthy individuals vs 82 renal transplant recipients, a SNP in LILRB1 (rs1061680) has been shown to associate with increased carotid intimal media thickness (192) but additional comprehensive studies evaluating LILRB1 expression or genetic variation in kidney transplantation are lacking. By comparing 90 patients with a functional renal allograft and 40 patients rejecting their transplant, Ajith et al confirmed the protective effect of high levels of the soluble HLA-G dimers (193). They also studied the underlying mechanism by genomic-and cellular analysis of patient derived T cells and in LILRB1 transgenic mouse models.…”

Section: Hla-g As Immune Checkpoint For Nk Cells Expressing Kir2dl4 And/or Lilrb1mentioning

confidence: 98%

HLA Class I Molecules as Immune Checkpoints for NK Cell Alloreactivity and Anti-Viral Immunity in Kidney Transplantation

et al. 2021

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Natural killer (NK) cells are innate lymphocytes that can kill diseased- or virally-infected cells, mediate antibody dependent cytotoxicity and produce type I immune-associated cytokines upon activation. NK cells also contribute to the allo-immune response upon kidney transplantation either by promoting allograft rejection through lysis of cells of the transplanted organ or by promoting alloreactive T cells. In addition, they protect against viral infections upon transplantation which may be especially relevant in patients receiving high dose immune suppression. NK cell activation is tightly regulated through the integrated balance of signaling via inhibitory- and activating receptors. HLA class I molecules are critical regulators of NK cell activation through the interaction with inhibitory- as well as activating NK cell receptors, hence, HLA molecules act as critical immune checkpoints for NK cells. In the current review, we evaluate how NK cell alloreactivity and anti-viral immunity are regulated by NK cell receptors belonging to the KIR family and interacting with classical HLA class I molecules, or by NKG2A/C and LILRB1/KIR2DL4 engaging non-classical HLA-E or -G. In addition, we provide an overview of the methods to determine genetic variation in these receptors and their HLA ligands.

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HLA‐G dimer targets Granzyme B pathway to prolong human renal allograft survival

Cited by 20 publications

References 52 publications

Got your mother in a whirl: The role of maternal T cells and myeloid cells in pregnancy

Got your mother in a whirl: The role of maternal T cells and myeloid cells in pregnancy

Humanized Mouse Model as a Novel Approach in the Assessment of Human Allogeneic Responses in Organ Transplantation

HLA Class I Molecules as Immune Checkpoints for NK Cell Alloreactivity and Anti-Viral Immunity in Kidney Transplantation

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