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1.
Cell Mol Immunol ; 20(5): 489-511, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36973489

RESUMO

Chronic antigenic stimulation can trigger the differentiation of antigen-experienced CD4+ T cells into T regulatory type 1 (TR1) cells, a subset of interleukin-10-producing Treg cells that do not express FOXP3. The identities of the progenitor(s) and transcriptional regulators of this T-cell subset remain unclear. Here, we show that the peptide-major histocompatibility complex class II (pMHCII) monospecific immunoregulatory T-cell pools that arise in vivo in different genetic backgrounds in response to pMHCII-coated nanoparticles (pMHCII-NPs) are invariably comprised of oligoclonal subpools of T follicular helper (TFH) and TR1 cells with a nearly identical clonotypic composition but different functional properties and transcription factor expression profiles. Pseudotime analyses of scRNAseq data and multidimensional mass cytometry revealed progressive downregulation and upregulation of TFH and TR1 markers, respectively. Furthermore, pMHCII-NPs trigger cognate TR1 cell formation in TFH cell-transfused immunodeficient hosts, and T-cell-specific deletion of Bcl6 or Irf4 blunts both the TFH expansion and TR1 formation induced by pMHCII-NPs. In contrast, deletion of Prdm1 selectively abrogates the TFH-to-TR1 conversion. Bcl6 and Prdm1 are also necessary for anti-CD3 mAb-induced TR1 formation. Thus, TFH cells can differentiate into TR1 cells in vivo, and BLIMP1 is a gatekeeper of this cellular reprogramming event.


Assuntos
Células T Auxiliares Foliculares , Linfócitos T Auxiliares-Indutores , Regulação da Expressão Gênica , Subpopulações de Linfócitos T , Linfócitos T Reguladores , Diferenciação Celular , Antígenos/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Centro Germinativo
2.
J Control Release ; 338: 557-570, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34474072

RESUMO

Nanoparticles (NPs) coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHCs) can blunt autoimmune diseases by re-programming cognate effector T-lymphocytes into disease-suppressing regulatory T-cells, followed by massive expansion. Here, a method to quantify the absolute amounts of the active drug product is developed, to understand the relationship between bioavailability and pharmacodynamics. Incubation with plasma results in the formation of a protein corona that stabilizes the directional pMHC coat, shielding it from proteolysis or anti-drug antibody recognition, without any appreciable loss in biological potency. A quantitative method that harnesses these features indicates that the half-life of these compounds in the circulation and organs is an order of magnitude shorter (minutes vs. hours) than that measured using commonly-used semi-quantitative methods. Extensive transmission electron microscopy-based organ scanning and flow cytometry-based enumeration of pMHCII-NP capturing cells confirmed that these compounds are rapidly captured (within 1 min) by liver sinusoidal endothelial cells, Kupffer cells, splenic phagocytes and cognate T-cells, leading to a fast decline in the circulation. Therefore, the powerful pharmacodynamic effects of these compounds are dissociated from long bioavailability, implying a hit-and-run event. Collectively, these data provide a detailed view of the life-cycle of a nanoimmunomedicine, and suggest that the real half-lives of intact nanomedicines may be much shorter than those estimated using indirect approaches.


Assuntos
Doenças Autoimunes , Nanomedicina , Autoantígenos , Disponibilidade Biológica , Células Endoteliais , Humanos
3.
Cell Rep ; 34(13): 108919, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33789099

RESUMO

Neutrophils with immunoregulatory properties, also referred to as type-2 neutrophils (N2), myeloid-derived suppressor cells (MDSCs), or tumor-associated neutrophils (TANs), comprise a heterogeneous subset of cells that arise from unknown precursors in response to poorly understood cues. Here, we find that, in several models of liver autoimmunity, pharmacologically induced, autoantigen-specific T regulatory type-1 (TR1) cells and TR1-cell-induced B regulatory (Breg) cells use five immunoregulatory cytokines to coordinately recruit neutrophils into the liver and program their transcriptome to generate regulatory neutrophils. The liver-associated neutrophils from the treated mice, unlike their circulating counterparts or the liver neutrophils of sick mice lacking antigen-specific TR1 cells, are proliferative, can transfer disease protection to immunocompromised hosts engrafted with pathogenic effectors, and blunt antigen-presentation and local autoimmune responses via cathelin-related anti-microbial peptide (CRAMP), a cathelicidin, in a CRAMP-receptor-dependent manner. These results, thus, identify antigen-specific regulatory T cells as drivers of tissue-restricted regulatory neutrophil formation and CRAMP as an effector of regulatory neutrophil-mediated immunoregulation.


Assuntos
Autoimunidade , Catelicidinas/metabolismo , Fígado/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos/metabolismo , Linfócitos B Reguladores/imunologia , Polaridade Celular/genética , Citocinas/metabolismo , Regulação da Expressão Gênica , Inflamação/patologia , Células de Kupffer/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Mitose/genética , Células Supressoras Mieloides/imunologia , Infiltração de Neutrófilos , Neutrófilos , Especificidade de Órgãos , Fenótipo , Transcrição Gênica
4.
Nat Commun ; 8: 14419, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28176764

RESUMO

The thymus is an organ that produces functionally competent T cells that protect us from pathogens and malignancies. Foxn1 is a transcription factor that is essential for thymus organogenesis; however, the direct target for Foxn1 to actuate thymic T-cell production is unknown. Here we show that a Foxn1-binding cis-regulatory element promotes the transcription of ß5t, which has an essential role in cortical thymic epithelial cells to induce positive selection of functionally competent CD8+ T cells. A point mutation in this genome element results in a defect in ß5t expression and CD8+ T-cell production in mice. The results reveal a Foxn1-ß5t transcriptional axis that governs CD8+ T-cell production in the thymus.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/fisiologia , Complexo de Endopeptidases do Proteassoma/genética , Timo/fisiologia , Animais , Diferenciação Celular/genética , Células Cultivadas , Células Epiteliais/fisiologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , Mutação Puntual , Elementos Reguladores de Transcrição/fisiologia , Timo/citologia , Técnicas de Cultura de Tecidos
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