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1.
Immunity ; 57(7): 1586-1602.e10, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38897202

RESUMO

The tissues are the site of many important immunological reactions, yet how the immune system is controlled at these sites remains opaque. Recent studies have identified Foxp3+ regulatory T (Treg) cells in non-lymphoid tissues with unique characteristics compared with lymphoid Treg cells. However, tissue Treg cells have not been considered holistically across tissues. Here, we performed a systematic analysis of the Treg cell population residing in non-lymphoid organs throughout the body, revealing shared phenotypes, transient residency, and common molecular dependencies. Tissue Treg cells from different non-lymphoid organs shared T cell receptor (TCR) sequences, with functional capacity to drive multi-tissue Treg cell entry and were tissue-agnostic on tissue homing. Together, these results demonstrate that the tissue-resident Treg cell pool in most non-lymphoid organs, other than the gut, is largely constituted by broadly self-reactive Treg cells, characterized by transient multi-tissue migration. This work suggests common regulatory mechanisms may allow pan-tissue Treg cells to safeguard homeostasis across the body.


Assuntos
Movimento Celular , Linfócitos T Reguladores , Linfócitos T Reguladores/imunologia , Animais , Camundongos , Movimento Celular/imunologia , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Fatores de Transcrição Forkhead/metabolismo , Especificidade de Órgãos/imunologia , Homeostase/imunologia
2.
Immunity ; 57(3): 541-558.e7, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38442708

RESUMO

Cancer patients often receive a combination of antibodies targeting programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA4). We conducted a window-of-opportunity study in head and neck squamous cell carcinoma (HNSCC) to examine the contribution of anti-CTLA4 to anti-PD-L1 therapy. Single-cell profiling of on- versus pre-treatment biopsies identified T cell expansion as an early response marker. In tumors, anti-PD-L1 triggered the expansion of mostly CD8+ T cells, whereas combination therapy expanded both CD4+ and CD8+ T cells. Such CD4+ T cells exhibited an activated T helper 1 (Th1) phenotype. CD4+ and CD8+ T cells co-localized with and were surrounded by dendritic cells expressing T cell homing factors or antibody-producing plasma cells. T cell receptor tracing suggests that anti-CTLA4, but not anti-PD-L1, triggers the trafficking of CD4+ naive/central-memory T cells from tumor-draining lymph nodes (tdLNs), via blood, to the tumor wherein T cells acquire a Th1 phenotype. Thus, CD4+ T cell activation and recruitment from tdLNs are hallmarks of early response to anti-PD-L1 plus anti-CTLA4 in HNSCC.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Antígeno B7-H1/genética , Antígeno CTLA-4 , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Linfócitos T CD4-Positivos , Microambiente Tumoral
3.
Bioinformatics ; 37(19): 3220-3227, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33830183

RESUMO

MOTIVATION: Identifying rare subpopulations of cells is a critical step in order to extract knowledge from single-cell expression data, especially when the available data is limited and rare subpopulations only contain a few cells. In this paper, we present a data mining method to identify small subpopulations of cells that present highly specific expression profiles. This objective is formalized as a constrained optimization problem that jointly identifies a small group of cells and a corresponding subset of specific genes. The proposed method extends the max-sum submatrix problem to yield genes that are, for instance, highly expressed inside a small number of cells, but have a low expression in the remaining ones. RESULTS: We show through controlled experiments on scRNA-seq data that the MicroCellClust method achieves a high F1 score to identify rare subpopulations of artificially planted human T cells. The effectiveness of MicroCellClust is confirmed as it reveals a subpopulation of CD4 T cells with a specific phenotype from breast cancer samples, and a subpopulation linked to a specific stage in the cell cycle from breast cancer samples as well. Finally, three rare subpopulations in mouse embryonic stem cells are also identified with MicroCellClust. These results illustrate the proposed method outperforms typical alternatives at identifying small subsets of cells with highly specific expression profiles. AVAILABILITYAND IMPLEMENTATION: The R and Scala implementation of MicroCellClust is freely available on GitHub, at https://github.com/agerniers/MicroCellClust/ The data underlying this article are available on Zenodo, at https://dx.doi.org/10.5281/zenodo.4580332. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

4.
Clin Cancer Res ; 29(2): 309-315, 2023 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-36044396

RESUMO

T cells are key effectors of our immune response against tumors and exert their antitumor effects upon recognizing a variety of tumor-specific peptides presented by HLA molecules on the surface of tumor cells. The identification of the tumor-specific antigens of a given tumor is not required for immune checkpoint therapy (ICT), which mainly reactivates existing tumor-specific T cells together with T cells of unknown specificities. To decrease the activation of non-tumor-specific T cells, active or passive immunizations against tumor-specific antigens are considered. These immunizations require the identification of at least some of the tumor-specific antigens displayed on the tumor cells of a patient. While this has become an easy task for tumors with a large number of mutations generating neoantigens, it remains difficult for the remainder. Here, we review some facts about human tumor-specific or tumor-associated antigens, as well as some hopes for their future use in cancer immunotherapy.


Assuntos
Neoplasias , Linfócitos T , Humanos , Neoplasias/genética , Antígenos de Neoplasias , Imunoterapia
5.
Nat Commun ; 14(1): 7825, 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38030622

RESUMO

The combination of atezolizumab plus bevacizumab (atezo/bev) has dramatically changed the treatment landscape of advanced HCC (aHCC), achieving durable responses in some patients. Using single-cell transcriptomics, we characterize the intra-tumoural and peripheral immune context of patients with aHCC treated with atezo/bev. Tumours from patients with durable responses are enriched for PDL1+ CXCL10+ macrophages and, based on cell-cell interaction analysis, express high levels of CXCL9/10/11 and are predicted to attract peripheral CXCR3+ CD8+ effector-memory T cells (CD8 TEM) into the tumour. Based on T cell receptor sharing and pseudotime trajectory analysis, we propose that CD8 TEM preferentially differentiate into clonally-expanded PD1- CD45RA+ effector-memory CD8+ T cells (CD8 TEMRA) with pronounced cytotoxicity. In contrast, in non-responders, CD8 TEM remain frozen in their effector-memory state. Finally, in responders, CD8 TEMRA display a high degree of T cell receptor sharing with blood, consistent with their patrolling activity. These findings may help understand the possible mechanisms underlying response to atezo/bev in aHCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Linfócitos T CD8-Positivos , Carcinoma Hepatocelular/tratamento farmacológico , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Receptor de Morte Celular Programada 1 , Células T de Memória , Neoplasias Hepáticas/tratamento farmacológico , Antígenos Comuns de Leucócito , Macrófagos , Receptores de Antígenos de Linfócitos T , Quimiocina CXCL10
6.
Biomolecules ; 12(10)2022 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-36291702

RESUMO

In type 1 diabetes, dysfunctional glucose regulation occurs due to the death of insulin-producing beta-cells in the pancreatic islets. Initiation of this process is caused by the inheritance of an adaptive immune system that is predisposed to responding to beta-cell antigens, most notably to insulin itself, coupled with unknown environmental insults priming the autoimmune reaction. While autoimmunity is a primary driver in beta-cell death, there is growing evidence that cellular stress participates in the loss of beta-cells. In the beta-cell fragility model, partial loss of islet mass requires compensatory upregulation of insulin production in the remaining islets, driving a cellular stress capable of triggering apoptosis in the remaining cells. The Glis3-Manf axis has been identified as being pivotal to the relative fragility or robustness of stressed islets, potentially operating in both type 1 and type 2 diabetes. Here, we have used an AAV-based gene delivery system to enhance the expression of the anti-apoptotic protein Manf in the beta-cells of NOD mice. Gene delivery substantially lowered the rate of diabetes development in treated mice. Manf-treated mice demonstrated minimal insulitis and superior preservation of insulin production. Our results demonstrating the therapeutic potential of Manf delivery to enhance beta-cell robustness and avert clinical diabetes.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Camundongos , Animais , Camundongos Endogâmicos NOD , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/prevenção & controle , Ilhotas Pancreáticas/metabolismo , Insulina/genética , Técnicas de Transferência de Genes , Glucose , Proteínas Reguladoras de Apoptose/genética , Fatores de Crescimento Neural
7.
J Exp Med ; 219(7)2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35699942

RESUMO

Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.


Assuntos
Interleucina-2 , Células Matadoras Naturais , Linfócitos T Reguladores , Animais , Imunidade Inata , Interleucina-2/biossíntese , Interleucina-2/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
8.
Nat Commun ; 11(1): 4545, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917858

RESUMO

TGF-ß1, ß2 and ß3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-ß inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-ß1 production by Tregs with antibodies against GARP:TGF-ß1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-ß1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8+ T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-ß1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-ß1 mAbs, by selectively blocking a single TGF-ß isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/imunologia , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
9.
Immun Inflamm Dis ; 5(3): 346-354, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28508570

RESUMO

INTRODUCTION: While most transcripts arising from the human T Cell Receptor locus reflect fully rearranged genes, several germline transcripts have been identified. We describe a new germline transcript arising from the human TCRB locus. METHODS: cDNA sequencing, promoter, and gene expression analyses were used to characterize the new transcript. RESULTS: The new germline transcript encoded by the human TCRB locus consists of a new exon of 103 bp, which we named TRBX1 (X1), spliced with the first exon of gene segments Cß1 or Cß2. X1 is located upstream of gene segment Dß1 and is therefore deleted from a V-DJ rearranged TCRB locus. The X1-Cß transcripts do not appear to code for a protein. We define their transcription start and minimal promoter. These transcripts are found in populations of mature T lymphocytes from blood or tissues and in T cell clones with a monoallelic TCRB rearrangement. In immature thymocytes, they are already detectable in CD1a- CD34+ CD4- CD8- cells, therefore before completion of the TCRB rearrangements. CONCLUSIONS: The X1 promoter appears to be the ortholog of the mouse pre-Dß1 promoter (PDß1). Like PDß1, its activation is regulated by Eß in T cells and might facilitate the TCRB rearrangement process by contributing to the accessibility of the Dß1 locus.


Assuntos
Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Loci Gênicos , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Transcrição Gênica , Animais , Humanos , Camundongos , RNA Mensageiro/biossíntese
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