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  • The American Association of Immunologists  (87)
  • 1
    Online Resource
    Online Resource
    CD28 Costimulation Is Essential for Human T Regulatory Expansion and Function
    The American Association of Immunologists ; 2008
    In:  The Journal of Immunology Vol. 181, No. 4 ( 2008-08-15), p. 2855-2868
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 181, No. 4 ( 2008-08-15), p. 2855-2868
    Abstract: The costimulatory requirements required for peripheral blood T regulatory cells (Tregs) are unclear. Using cell-based artificial APCs we found that CD28 but not ICOS, OX40, 4-1BB, CD27, or CD40 ligand costimulation maintained high levels of Foxp3 expression and in vitro suppressive function. Only CD28 costimulation in the presence of rapamycin consistently generated Tregs that consistently suppressed xenogeneic graft-vs-host disease in immunodeficient mice. Restimulation of Tregs after 8–12 days of culture with CD28 costimulation in the presence of rapamycin resulted in & gt;1000-fold expansion of Tregs in & lt;3 wk. Next, we determined whether other costimulatory pathways could augment the replicative potential of CD28-costimulated Tregs. We observed that while OX40 costimulation augmented the proliferative capacity of CD28-costimulated Tregs, Foxp3 expression and suppressive function were diminished. These studies indicate that the costimulatory requirements for expanding Tregs differ from those for T effector cells and, furthermore, they extend findings from mouse Tregs to demonstrate that human postthymic Tregs require CD28 costimulation to expand and maintain potent suppressive function in vivo.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.181.4.2855
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2008
    detail.hit.zdb_id: 1475085-5
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  • 2
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    Online Resource
    Gastrointestinal Cells of IL-7 Receptor Null Mice Exhibit Increased Sensitivity to Irradiation
    The American Association of Immunologists ; 2001
    In:  The Journal of Immunology Vol. 166, No. 5 ( 2001-03-01), p. 2923-2928
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 166, No. 5 ( 2001-03-01), p. 2923-2928
    Abstract: IL-7 is a critical cytokine in the development of T and B cells but little is known about its activity on nonhematopoietic cells. An unexpected finding was noted in allogeneic bone marrow transplant studies using IL-7 receptor null (IL-7Rα−/−) mice as recipients. These mice exhibited a significantly greater weight loss after total body irradiation compared with wild type, IL-7Rα+/+, mice. Pathological assessment indicated greater intestinal crypt damage in IL-7Rα−/− recipients, suggesting these mice may be predisposed to gut destruction. Therefore, we determined the effect of the conditioning itself on the intestinal tract of these mice. IL-7Rα−/− mice and IL-7Rα+/+ mice were irradiated and examined for lesions and apoptosis within the small intestine. In moribund animals, IL-7Rα−/− mice had extensive damage in the small intestine, including marked ablation of the crypts and extreme shortening of villi following 1500 cGy total body irradiation. In contrast, by 8 days after irradiation, the small intestines of IL-7Rα+/+ mice had regenerated as distinguished by normal villus length and hyperplastic crypts. Following 750 cGy irradiation, IL-7Rα−/− mice had a higher proportion of apoptotic cells in the crypts and an accompanying increase in the pro-apoptotic protein Bak was expressed in intestinal epithelial cells. These results demonstrate the increased radiosensitivity of intestinal stem cells within the crypts in IL-7Rα−/− mice and a role for IL-7 in the protection of radiation-induced apoptosis in these same cells. This study describes a novel role of IL-7 in nonhematopoietic tissues.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.166.5.2923
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2001
    detail.hit.zdb_id: 1475085-5
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  • 3
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    Online Resource
    Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome.
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1_Supplement ( 2017-05-01), p. 82.8-82.8
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 82.8-82.8
    Abstract: Donor T cell-derived IL-17A can mediate late immunopathology in graft-versus-host disease (GVHD), however protective roles remain unclear. Using multiple cytokine and cytokine receptor subunit knockout mice we demonstrate that stem cell transplant (SCT) recipients lacking the ability to generate or signal IL-17 develop intestinal hyper-acute GVHD. This protective effect is restricted to the molecular interaction of IL-17A and/or IL-17F with the IL-17RA/C receptor. The protection from GVHD afforded by IL-17A required secretion from, and signaling in, both hematopoietic and non-hematopoietic host tissue. Given the intestinal-specificity of the disease in these animals, we hypothesized a microbiome contribution. Cohousing of WT with IL-17RA and IL-17RC deficient mice, dramatically enhanced the susceptibility of WT mice to acute GVHD. Furthermore, the gut microbiome of WT mice shifted towards that of the IL-17RA/C mice during cohousing prior to transplant, confirming that IL-17-sensitive gut microbiota controls susceptibility to acute GVHD. Finally, induced IL-17A deletion peri-transplant also enhanced acute GVHD, consistent with an additional protective role for this cytokine independent of effects on dysbiosis. Importantly, this implies that blocking IL-17 in a clinical trial could have adverse effects via dysbiosis, particularly in the early post-transplant setting and raises caution about their potential effects if used long term.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.198.Supp.82.8
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
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  • 4
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    Online Resource
    Notch Signaling at Later Stages of NK Cell Development Enhances KIR Expression and Functional Maturation
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 193, No. 7 ( 2014-10-01), p. 3344-3354
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 193, No. 7 ( 2014-10-01), p. 3344-3354
    Abstract: The Notch signaling pathway plays a substantial role in human NK cell development. However, the role of Notch on killer Ig–like receptor (KIR) upregulation and acquisition of effector function has not been explored. To evaluate how Notch influences terminal differentiation, cord blood–derived NK cells or sorted peripheral blood NK cells were cultured with IL-15 for 7 d with inhibitory or activating Notch signals. Inhibition of Notch signaling significantly decreased KIR expression, whereas activation enhanced it. Overexpression of activated Notch on cord blood–derived NK cells resulted in a 2-fold increase in KIR expression, indicating that Notch signaling plays a direct, cell-intrinsic role in KIR regulation. Moreover, Notch-mediated KIR expression on NK cells is regulated through cis inhibition by delta-like ligand 1. Notch signaling also enhances CD16 upregulation that precedes KIR expression. Concomitant with the upregulation of KIR and CD16, Notch signaling induces increased cytolytic effector capacity and cytokine secretion, even in posttransplant samples in which NK cell function is inherently defective. Given these attributes of Notch signaling, we propose that Notch agonists may enhance NK cell maturation and tumor killing in a posttransplant setting.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1400534
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
    detail.hit.zdb_id: 1475085-5
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  • 5
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    Online Resource
    IL-33 Is an Unconventional Alarmin That Stimulates IL-2 Secretion by Dendritic Cells To Selectively Expand IL-33R/ST2+ Regulatory T Cells
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 193, No. 8 ( 2014-10-15), p. 4010-4020
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 193, No. 8 ( 2014-10-15), p. 4010-4020
    Abstract: IL-33 is a recently characterized IL-1 family member that is proposed to function as an alarmin, or endogenous signal of cellular damage, as well as act as a pleiotropic cytokine. The ability of IL-33 to potentiate both Th1 and Th2 immunity supports its role in pathogen clearance and disease immunopathology. Yet, IL-33 restrains experimental colitis and transplant rejection by expanding regulatory T cells (Treg) via an undefined mechanism. We sought to determine the influence of IL-33 on hematopoietic cells that drives Treg expansion and underlies the therapeutic benefit of IL-33 administration. In this study, we identify a feedback loop in which conventional mouse CD11c+ dendritic cells (DC) stimulated by IL-33 secrete IL-2 to selectively expand IL-33R(ST2+)– suppressive CD4+Foxp3+ Treg. Interestingly, this occurs in the absence of classical DC maturation, and DC-derived (innate) IL-2 increases ST2 expression on both DC and interacting Treg. ST2+ Treg represent an activated subset of Foxp3+ cells, demonstrated to be ICOShighCD44high compared with their ST2− counterparts. Furthermore, although studies have shown that IL-33–exposed DC promote Th2 responses, we reveal that ST2+ DC are required for IL-33–mediated in vitro and in vivo Treg expansion. Thus, we have uncovered a relationship between IL-33 and innate IL-2 that promotes the selective expansion of ST2+ Treg over non-Treg. These findings identify a novel regulatory pathway driven by IL-33 in immune cells that may be harnessed for therapeutic benefit or for robust expansion of Treg in vitro and in vivo.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1400481
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
    detail.hit.zdb_id: 1475085-5
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  • 6
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    Online Resource
    Recipient conditioning contributes to IL-33-driven Th1 alloimmune responses following rapid ST2 upregulation on donor CD4+ T cells during lymphopenia-induced proliferation
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 1_Supplement ( 2018-05-01), p. 55.4-55.4
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 55.4-55.4
    Abstract: IL-33 is augmented in recipient tissues by conditioning before allogeneic stem cell transplantation (alloSCT) and is a required signal to donor T cell for GVHD. Targetable mechanisms by which IL-33 supports GVHD are yet undefined. Conditioning causes lymphopenia-induced proliferation (LIP) and releases microbial products. These products promote myeloid cell secretion of IL-12, which induces the IL-33 receptor, ST2, on T cells in vitro. We hypothesized that IL-12 induces ST2 on donor T cells during LIP promoting IL-33 augmentation of the Th1 responses leading to GVHD. To establish the role of IL-12 in T cell ST2 expression and IL-33-mediated GVHD, irradiated BALB/c mice were given B6 alloSCT and T cells. Some mice received IL-12p40 neutralizing Ab or control Ab alone, with or without concurrent IL-33 administration. To test the impact of lymphopenia on T cells, ST2−Foxp3−CD4+ T cells alone or with ST2+ Treg were transferred into B6 Rag2−/−γc−/− mice. Mice received PBS or IL-33 on days 1–8. Neutralizing IL-12 did not reduce ST2 on T cells after alloSCT nor rescue mice from IL-33-mediated acceleration of GVHD. Post-alloSCT, IL-33 worked with IL-12 to expand ST2+Tbet+ Th1 cells. Neutralizing IL-12, but not delivery of IL-33, increased Gata3+ Th2 cells after alloSCT. During LIP, CD4+Foxp3− T cells rapidly upregulated ST2 independent of IL-33, but IL-33 then favored the expansion of Th1 cells, even in the presence of ST2+ Treg. These data suggest that CD4+ T cells rapidly upregulate ST2 during alloSCT conditioning induced lymphopenia. After alloSCT, IL-33 does not support Treg or Th2 cells, but works with IL-12 to augment Th1 responses and GVHD. Blocking stimuli that induces ST2 on proliferating donor CD4+ T cells may be effective for limiting GVHD.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.200.Supp.55.4
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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  • 7
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    Online Resource
    Umbilical Cord Blood T Cells Express Multiple Natural Cytotoxicity Receptors after IL-15 Stimulation, but Only NKp30 Is Functional
    The American Association of Immunologists ; 2008
    In:  The Journal of Immunology Vol. 181, No. 7 ( 2008-10-01), p. 4507-4515
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 181, No. 7 ( 2008-10-01), p. 4507-4515
    Abstract: The natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46 are thought to be NK lineage restricted. Herein we show that IL-15 induces NCR expression on umbilical cord blood (UCB) T cells. NCRs were mainly on CD8+ and CD56+ UCB T cells. Only NKp30 was functional as demonstrated by degranulation, IFN-γ release, redirected killing, and apoptosis. Since NCRs require adaptor proteins for function, the expressions of these adaptors were determined. The adaptors used by NKp30 and NKp46, FcεR1γ and CD3ζ, were detected in UCB T cells. There was a near absence of DAP12, the adaptor for NKp44, consistent with a hypofunctional state. NKp46 was on significantly fewer UCB T cells, possibly accounting for its lack of function. Adult peripheral blood (PB) T cells showed minimal NCR acquisition after culture with IL-15. Since UCB contains a high frequency of naive T cells, purified naive T cells from adult PB were tested. Although NKp30 was expressed on a small fraction of naive PB T cells, it was nonfunctional. In contrast to UCB, PB T cells lacked FcεR1γ expression. These results demonstrate differences between UCB and PB T cells regarding NCR expression and function. Such findings challenge the concept that NCRs are NK cell specific.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.181.7.4507
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2008
    detail.hit.zdb_id: 1475085-5
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  • 8
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    Online Resource
    CD30/CD30 Ligand (CD153) Interaction Regulates CD4+ T Cell-Mediated Graft-versus-Host Disease
    The American Association of Immunologists ; 2004
    In:  The Journal of Immunology Vol. 173, No. 5 ( 2004-09-01), p. 2933-2941
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 173, No. 5 ( 2004-09-01), p. 2933-2941
    Abstract: CD30, a TNFR family member, is expressed on activated CD4+ and CD8+ T cells and B cells and is a marker of Hodgkin’s lymphoma; its ligand, CD30L (CD153) is expressed by activated CD4+ and CD8+ T cells, B cells, and macrophages. Signaling via CD30 can lead to proliferation or cell death. CD30-deficient (−/−) mice have impaired thymic negative selection and increased autoreactivity. Although human alloreactive T cells preferentially reside within the CD30+ T cell subset, implicating CD30 as a regulator of T cell immune responses, the role of CD30/CD153 in regulating graft-vs-host disease (GVHD) has not been reported. We used a neutralizing anti-CD153 mAb, CD30−/− donor mice, and generated CD153−/− recipient mice to analyze the effect of CD30/CD153 interaction on GVHD induction. Our data indicate that the CD30/CD153 pathway is a potent regulator of CD4+, but not CD8+, T cell-mediated GVHD. Although blocking CD30/CD153 interactions in vivo did not affect alloreactive CD4+ T cell proliferation or apoptosis, a substantial reduction in donor CD4+ T cell migration into the gastrointestinal tract was readily observed with lesser effects in other GVHD target organs. Blockade of the CD30/CD153 pathway represents a new approach for preventing CD4+ T cell-mediated GVHD.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.173.5.2933
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2004
    detail.hit.zdb_id: 1475085-5
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  • 9
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    B7-H4 expression in donor T cells and host cells negatively regulates acute graftversus- host disease lethality
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 202, No. 1_Supplement ( 2019-05-01), p. 69.10-69.10
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 69.10-69.10
    Abstract: The B7 family members are critical in positive and negative regulation of immune responses by engaging various lymphocyte receptors. B7-H4 is a member of the B7 family that can negatively regulate T cell function. We investigated the role of host and donor B7-H4 in regulating acute graft-versus-host disease (GVHD). Allogeneic donor T cells infused into B7-H4−/− versus wild type (WT) recipients markedly accelerated GVHD-induced lethality in a C57BL/6 to BALB/c GVHD model. Chimera studies pointed toward B7-H4 expression on host hematopoietic cells as more critical than parenchymal cells in controlling GVHD. B7-H4−/− recipients had rapid mortality associated with increased donor T cell expansion, gut T cell homing and loss of intestinal epithelial integrity, increased Teffector function (proliferation, pro-inflammatory cytokines, cytolytic molecules) and reduced apoptosis. Higher metabolic demands of rapidly proliferating donor T cells in B7-H4−/− versus WT recipients required multiple metabolic pathways, increased extra-cellular acidification rates and oxygen consumption rates, and increased expression of fuel substrate transporters. Interestingly, during GVHD, B7-H4 expression was upregulated on allogeneic WT donor T cells. Consistent with these data, donor B7-H4−/− T cells given to WT recipients increased GVHD mortality and functioned similarly to WT T cells from allogeneic B7-H4−/− recipients. Graft-versus-leukemia responses were intact regardless as to whether B7-H4−/− mice were used as hosts or donors. Taken together, these data provide new insights into the negative regulatory processes that control GVHD and provide support for developing therapeutic strategies directed toward the B7-H4 pathway.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.202.Supp.69.10
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
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  • 10
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    Online Resource
    Correction: B Cells Drive Autoimmunity in Mice with CD28-Deficient Regulatory T Cells
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 7 ( 2018-04-01), p. 2505-2506
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 7 ( 2018-04-01), p. 2505-2506
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1800150
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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