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1.
Nat Immunol ; 21(10): 1205-1218, 2020 10.
Article in English | MEDLINE | ID: mdl-32839608

ABSTRACT

Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Inflammation/immunology , Killer Cells, Natural/immunology , Leishmania donovani/physiology , Leishmaniasis, Visceral/immunology , Malaria/immunology , Membrane Proteins/metabolism , Plasmodium/physiology , Animals , Cells, Cultured , Cytotoxicity, Immunologic , Disease Models, Animal , Exocytosis , Humans , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Secretory Vesicles/metabolism
3.
Cytotherapy ; 26(7): 719-728, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38530690

ABSTRACT

BACKGROUND AIMS: Regulatory T cells (Tregs) are the main mediators of peripheral tolerance. Treg-directed therapy has shown promising results in preclinical studies of diverse immunopathologies. At present, the clinical applicability of adoptive Treg transfer is limited by difficulties in generating Tregs at sufficient cell dose and purity. METHODS: We developed a Good Manufacturing Practice (GMP) compliant method based on closed-system multiparametric Fluorescence-Activated Cell Sorting (FACS) to purify Tregs, which are then expanded in vitro and gene-marked with a clinical grade retroviral vector to enable in vivo fate tracking. Following small-scale optimization, we conducted four clinical-scale processing runs. RESULTS: We showed that Tregs could be enriched to 87- 92% purity following FACS-sorting, and expanded and transduced to yield clinically relevant cell dose of 136-732×106 gene-marked cells, sufficient for a cell dose of at least 2 × 106 cells/kg. The expanded Tregs were highly demethylated in the FOXP3 Treg-specific demethylated region (TSDR), consistent with bona fide natural Tregs. They were suppressive in vitro, but a small percentage could secrete proinflammatory cytokines, including interferon-γ and interleukin-17A. CONCLUSIONS: This study demonstrated the feasibility of isolating, expanding and gene-marking Tregs in clinical scale, thus paving the way for future phase I trials that will advance knowledge about the in vivo fate of transferred Tregs and its relationship with concomitant Treg-directed pharmacotherapy and clinical response.


Subject(s)
Flow Cytometry , Forkhead Transcription Factors , T-Lymphocytes, Regulatory , T-Lymphocytes, Regulatory/immunology , Humans , Flow Cytometry/methods , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Cell Separation/methods , Genetic Vectors/genetics
4.
J Clin Invest ; 134(7)2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38557487

ABSTRACT

Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.


Subject(s)
Bone Marrow Transplantation , Cytomegalovirus Infections , Immunity, Humoral , Interleukin-6 , Antiviral Agents , Bone Marrow Transplantation/adverse effects , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/metabolism , Immunoglobulin G , Interleukin-6/metabolism , Animals , Mice
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