iNKT cells coordinate immune pathways to enable engraftment in nonconditioned hosts

Hess, Nicholas J; Bharadwaj, Nikhila S; Bobeck, Elizabeth; McDougal, Courtney E; Ma, Shidong; Sauer, John-Demian; Hudson, Amy W.; Gumperz, Jenny E.

doi:10.26508/lsa.202000999

Cited by 6 publications

(8 citation statements)

References 69 publications

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“…To replicate our clinical observational study, we used a human xenogeneic transplant model wherein we transplanted various human graft tissues into immunodeficient mice ( 31 , 59 , 60 ). As we have published previously, xenogeneic GVHD (xeno-GVHD) is dose dependent with each human graft source having its own median lethal dose (LD 50 ) and that the development of xeno-GVHD is not donor dependent ( 59 ).…”

Section: Resultsmentioning

confidence: 99%

Inflammatory CD4/CD8 double-positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

et al. 2023

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An important paradigm in allogeneic hematopoietic cell transplantations (allo-HCTs) is the prevention of graft-versus-host disease (GVHD) while preserving the graft-versus-leukemia (GVL) activity of donor T cells. From an observational clinical study of adult allo-HCT recipients, we identified a CD4 + /CD8 + double-positive T cell (DPT) population, not present in starting grafts, whose presence was predictive of ≥ grade 2 GVHD. Using an established xenogeneic transplant model, we reveal that the DPT population develops from antigen-stimulated CD8 T cells, which become transcriptionally, metabolically, and phenotypically distinct from single-positive CD4 and CD8 T cells. Isolated DPTs were sufficient to mediate xeno-GVHD pathology when retransplanted into naïve mice but provided no survival benefit when mice were challenged with a human B-ALL cell line. Overall, this study reveals human DPTs as a T cell population directly involved with GVHD pathology.

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Section: Resultsmentioning

confidence: 99%

Inflammatory CD4/CD8 double-positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

et al. 2023

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“…To replicate our clinical observational study, we utilized a human xenogeneic transplant model wherein we transplanted various human graft tissue into immunodeficient mice 31,54,55 . As in our observational clinical study, we observed the presence of DPTs, which were not present in the starting healthy graft tissue, primarily developing in mice that would later develop lethal xenogeneic GVHD (Fig 2A).…”

Section: Resultsmentioning

confidence: 99%

“…To replicate our clinical observational study, we utilized a human xenogeneic transplant model wherein we transplanted various human graft tissue into immunodeficient mice 31,59,60 . As we have published previously, xenogeneic GVHD (xeno-GVHD) is dose-dependent with each human graft source possessing their own LD 50 dose and that the development of xeno-GVHD is not donor dependent 59 .…”

Section: Introductionmentioning

confidence: 99%

Inflammatory CD4/CD8 double positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

Hess

Turicek

Nadiminti

et al. 2022

Preprint

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Acute graft-vs-host disease (aGVHD) and tumor relapse remain the primary complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for malignant blood disorders. While post-transplant cyclophosphamide has reduced the overall prevalence and severity of aGVHD, relapse rates remain a concern. Thus, there remains a need to identify the specific human T cell subsets mediating GVHD pathology versus graft-versus-leukemia (GVL) effects. In xenogeneic transplantation studies using primary human cells from a variety of donors and tissue sources, we observed the development of a mature CD4+/CD8αβ+ double positive T cell (DPT) population in mice succumbing to lethal aGVHD but not in mice that failed to develop aGVHD. The presence of DPT, irrespective of graft source, was predictive of lethal GVHD as early as one week after xenogeneic transplantation. DPT co-express the master transcription factors of the CD8 and CD4 lineages, RUNX3 and THPOK respectively, and produce both cytotoxic and modulatory cytokines. To identify the origin of DPT, we transplanted isolated human CD4 or CD8 T cells, which in turn revealed that DPT only arise from the CD8 pool. Interestingly, re-transplantation of sorted CD8 T cells from GVHD mice did not reveal a second wave of DPT differentiation. Re-transplantation of flow-sorted DPT, CD8 or CD4 T cells from GVHD mice revealed that DPT are sufficient to mediate GVHD pathology but not GVL effects versus B-cell acute lymphoblastic leukemia. Lastly, we confirmed the presence and correlation of DPT with aGVHD pathology in a small cohort of allo-HSCT patients that developed grade 2-4 aGVHD in our clinic. Further understanding of DPT differentiation and pathology may lead to targeted prophylaxis and/or treatment regimens for aGVHD and potentially other human chronic inflammatory diseases.

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“…We also used a xenotransplantation model of hematopoietic engraftment to investigate the impact of the human iNKT-monocyte pathway in vivo . The addition of allogeneic adult iNKT cells to human cord blood mononuclear cell grafts resulted in dramatically improved engraftment, which was due to iNKT cells inducing cord blood monocytes to secrete prostaglandin E 2 , which potently suppressed T cell IFN-γ production ( 44 ). Since hematopoietic engraftment is suppressed by excessive IFN-γ ( 45 ), this analysis shows that human iNKT cells can engage powerful regulatory pathways that limit adverse effects of human T H1 activation in vivo .…”

Section: How Are the Anti-inflammatory Effects Of Inkt Cells Mediated?mentioning

confidence: 99%

“…Perhaps more importantly, polyfunctional human iNKT cells show a hierarchy of cytokine production in response to TCR stimulation that does not neatly segregate into clear T H1 or T H2 patterns. Weak TCR stimulation of human iNKT cells preferentially induces production of IL-3, GM-CSF, and IL-13, with increasing stimulation leading first to IFN-γ, then IL-4, then IL-2 ( 44 , 103 , 104 ) ( Figure 2D ). Secondary induction of NK cell IFN-γ secretion was associated with activation of human iNKT cells by strong TCR agonists ( 104 ).…”

Section: What Determines the Nature Of The Functional Response Mediat...mentioning

confidence: 99%

Harnessing invariant natural killer T cells to control pathological inflammation

Bharadwaj

Gumperz

2022

Front. Immunol.

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Invariant natural killer T (iNKT) cells are innate T cells that are recognized for their potent immune modulatory functions. Over the last three decades, research in murine models and human observational studies have revealed that iNKT cells can act to limit inflammatory pathology in a variety of settings. Since iNKT cells are multi-functional and can promote inflammation in some contexts, understanding the mechanistic basis for their anti-inflammatory effects is critical for effectively harnessing them for clinical use. Two contrasting mechanisms have emerged to explain the anti-inflammatory activity of iNKT cells: that they drive suppressive pathways mediated by other regulatory cells, and that they may cytolytically eliminate antigen presenting cells that promote excessive inflammatory responses. How these activities are controlled and separated from their pro-inflammatory functions remains a central question. Murine iNKT cells can be divided into four functional lineages that have either pro-inflammatory (NKT1, NKT17) or anti-inflammatory (NKT2, NKT10) cytokine profiles. However, in humans these subsets are not clearly evident, and instead most iNKT cells that are CD4+ appear oriented towards polyfunctional (TH0) cytokine production, while CD4- iNKT cells appear more predisposed towards cytolytic activity. Additionally, structurally distinct antigens have been shown to induce TH1- or TH2-biased responses by iNKT cells in murine models, but human iNKT cells may respond to differing levels of TCR stimulation in a way that does not neatly separate TH1 and TH2 cytokine production. We discuss the implications of these differences for translational efforts focused on the anti-inflammatory activity of iNKT cells.

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iNKT cells coordinate immune pathways to enable engraftment in nonconditioned hosts

Cited by 6 publications

References 69 publications

Inflammatory CD4/CD8 double-positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

Inflammatory CD4/CD8 double-positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

Inflammatory CD4/CD8 double positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

Harnessing invariant natural killer T cells to control pathological inflammation

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