Conserved and divergent aspects of human T‐cell development and migration in humanized mice

Halkias, Joanna; Yen, B. Linju; Taylor, Kayleigh T.; Reinhartz, Olaf; Winoto, Astar; Robey, Ellen; Melichar, Heather J.

doi:10.1038/icb.2015.38

Cited by 56 publications

(46 citation statements)

References 72 publications

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“…1b, d). Consistent with the reported decline in thymic production of PLZF + CD4 + T cells with advancing gestation 20,22 , PLZF + CD4 + T cells are essentially undetectable in term cord blood (CB) and adult peripheral blood (aPB), and we used aPB samples as internal controls between experiments (Extended Fig. 1a-b).…”

Section: Resultssupporting

confidence: 57%

CD161 mediates prenatal immune suppression of IFNγ-producing PLZF⁺T cells

Halkias

Rackaityte

Aran

et al. 2018

Preprint

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16While the fetal immune system defaults to a program of tolerance, there is concurrent 17 need for protective immunity to meet the antigenic challenges after birth. Activation of fetal T cells 18 is associated with fetal inflammation and the termination of pregnancy, yet which fetal T cells 19 contribute to this process is poorly understood. Here we show a transcriptionally distinct 20 population of pro-inflammatory T cells that predominates in the human fetal intestine. Activation of 21 PLZF + T cells results in rapid production of Th1 cytokines and is inhibited upon ligation of surface 22 CD161. This mechanism of fetal immune suppression may inform how immune dysregulation 23 could result in fetal and neonatal inflammatory pathologies such as preterm birth. Our data 24 support that human development of protective adaptive immunity originates in utero within the 25 specialized microenvironment of the fetal intestine. 26 27 INTRODUCTION 28 29The developing human immune system is uniquely adapted for fetal survival within the semi-30 allogeneic environment in utero as well as for neonatal protection after contact with the many 31 antigenic challenges encountered after birth. Unlike mice, which lack peripheral T cells in utero, 32 human T cells begin to populate peripheral organs (including mucosal sites) by 11-14 weeks of 33 gestation 1,2 . While naïve fetal T cells preferentially generate induced regulatory T cells upon 34 antigen encounter in the periphery 3 , there is evidence of protective fetal adaptive immunity in 35 response to pathogens and vaccines 4-6 . However, activated T cells are associated with the fetal 36 inflammatory response and contribute to the comorbidities associated with preterm birth 7-11 . The 37 concurrent development of fetal tolerogenic and protective T cell programs indicate that human 38 immune development may be more nuanced than previously appreciated. 40The presence of functional memory T cells in the fetus and infant [12][13][14][15] indicate that adaptive 41 immune memory originates in utero. However, the spatial compartmentalization of human T cell 42 differentiation and function suggests that the effector capacity of the fetal immune response 43 cannot be inferred from blood 13,16,17 . The existence of organized intestinal lymphoid structures as 44 early as the second trimester of gestation 18 , along with the environmental, maternal, and self-45 antigens within swallowed amniotic fluid, points to an instructive role for the intestinal mucosa in 46 the development of fetal adaptive immunity. 48In this study, we performed a detailed examination of fetal lymphoid and mucosal TCR CD4 + T 49 cells. We identified a polyclonal population of IFN-producing T cells characterized by expression 50 of the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF) and the C-type lectin 51 CD161. These Va7.2 -PLZF + CD161 + TCR + CD4 + T cells preferentially accumulate in the 52 lamina propria (LP) of the small intestine and possess a resident memory phenotype inferred 53 from ex...

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Section: Resultssupporting

confidence: 57%

CD161 mediates prenatal immune suppression of IFNγ-producing PLZF⁺T cells

Halkias

Rackaityte

Aran

et al. 2018

Preprint

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“…However, being a xenograft model, some aspects of the results should be interpreted with caution. Important T-cell subsets, such as regulatory T cells (40) and PLZF1…”

Section: Discussionmentioning

confidence: 99%

Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus

Brugman

Wiekmeijer

Eggermond

et al. 2015

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

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The fate and numbers of hematopoietic stem cells (HSC) and their progeny that seed the thymus constitute a fundamental question with important clinical implications. HSC transplantation is often complicated by limited T-cell reconstitution, especially when HSC from umbilical cord blood are used. Attempts to improve immune reconstitution have until now been unsuccessful, underscoring the need for better insight into thymic reconstitution. Here we made use of the NOD-SCID-IL-2Rγ−/− xenograft model and lentiviral cellular barcoding of human HSCs to study T-cell development in the thymus at a clonal level. Barcoded HSCs showed robust (>80% human chimerism) and reproducible myeloid and lymphoid engraftment, with T cells arising 12 wk after transplantation. A very limited number of HSC clones (<10) repopulated the xenografted thymus, with further restriction of the number of clones during subsequent development. Nevertheless, T-cell receptor rearrangements were polyclonal and showed a diverse repertoire, demonstrating that a multitude of T-lymphocyte clones can develop from a single HSC clone. Our data imply that intrathymic clonal fitness is important during T-cell development. As a consequence, immune incompetence after HSC transplantation is not related to the transplantation of limited numbers of HSC but to intrathymic events.H ematopoietic stem cell transplantation (HSCT) has become common clinical practice in the treatment of leukemia, lymphoma, and certain inherited immune and metabolic disorders. After transplantation there is an immediate need for de novo production of granulocytes, erythrocytes, and platelets, referred to as "hematopoietic reconstitution," later followed by recovery of lymphocyte numbers, termed "immune reconstitution." Although often successful, HSCT is associated with a number of complications arising from poor immune reconstitution, which presents one of the most important causes of morbidity after HSCT (1, 2). Poor myeloid reconstitution is directly linked to low numbers of HSCs in the transplant, but the reasons for poor immune and, in particular, T-lymphocyte reconstitution are much less clear.A study on the application of antithymocyte globulin in cord blood transplantation showed that antithymocyte globulin administration in pretransplantation conditioning results in decreased T-cell reconstitution and survival (3), indicating the need for a better understanding of de novo T-cell development after HSCT. As T cells develop in the thymus, in contrast to all other blood lineages that develop in the bone marrow (BM), HSCderived progenitors need to seed the thymus. Earlier work in mice has indicated that relatively few progenitors seed the thymus (4, 5), yet their numbers and the subsequent fate of the progeny derived from an HSC clone has remained elusive. The nature of the thymusseeding cell has been subject of much debate, certainly in humans. CD34+ cells (6, 7), CD34 (8), and others have been proposed as thymus-seeding cells in the human situation. In contrast to mice, the earliest hu...

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“…U-2OS 3D cells (1 × 10 6 ), mixed with 100 µl Matrigel, were injected subcutaneously (s.c.) in female non-obese diabetic (NOD) severe combined immunodeficiency (SCID) gamma mice engrafted with human hematopoietic CD34 + cells (Hu-CD34 + ; The Jackson Laboratories, Bar Harbor, MA), a model previously reported to have functional reconstituted VγVδ T-cells [30]. Mice were housed (5 per cage) under 12 h light/dark cycle, with food and drinking provided ad libitum.…”

Section: In Vivo Tumor Growthmentioning

confidence: 99%

“…Since mice have different VγVδ T-cell sets than humans [11], to verify whether NZ could reverse chemo-immune-resistance in preclinical models of osteosarcoma, we used Hu-CD34 + mice, characterized by functional Vγ9δ2 T-lymphocytes [30]. Mice were implanted with cells derived by chemo-immune-resistant 3D U-2OS cultures, treated with doxorubicin at the maximally tolerated dose [35], with or without NZ, at a dosage corresponding to that administered to patients treated with zoledronic acid.…”

Section: Increasing the Abca1/abcb1 Ratio Reduces The Growth Of Osteomentioning

confidence: 99%

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Belisario

Akman

Godel

et al. 2020

Cells

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The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor Vγ9Vδ2 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of Vγ9Vδ2 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and Vγ9Vδ2 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor α (LXRα); Ras/ERK1/2/HIF-1α axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and Vγ9Vδ2 T-cell infiltration. We suggest that the ABCB1 high ABCA1 low phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas.

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Conserved and divergent aspects of human T‐cell development and migration in humanized mice

Cited by 56 publications

References 72 publications

CD161 mediates prenatal immune suppression of IFNγ-producing PLZF⁺T cells

CD161 mediates prenatal immune suppression of IFNγ-producing PLZF⁺T cells

Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

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Conserved and divergent aspects of human T‐cell development and migration in humanized mice

Cited by 56 publications

References 72 publications

CD161 mediates prenatal immune suppression of IFNγ-producing PLZF+T cells

CD161 mediates prenatal immune suppression of IFNγ-producing PLZF+T cells

Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

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CD161 mediates prenatal immune suppression of IFNγ-producing PLZF⁺T cells

CD161 mediates prenatal immune suppression of IFNγ-producing PLZF⁺T cells