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1.
Front Immunol ; 15: 1391404, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38799444

RESUMEN

Introduction: Follicular Lymphoma (FL) results from the malignant transformation of germinal center (GC) B cells. FL B cells display recurrent and diverse genetic alterations, some of them favoring their direct interaction with their cell microenvironment, including follicular helper T cells (Tfh). Although FL-Tfh key role is well-documented, the impact of their regulatory counterpart, the follicular regulatory T cell (Tfr) compartment, is still sparse. Methods: The aim of this study was to characterize FL-Tfr phenotype by cytometry, gene expression profile, FL-Tfr origin by transcriptomic analysis, and functionality by in vitro assays. Results: CD4+CXCR5+CD25hiICOS+ FL-Tfr displayed a regulatory program that is close to classical regulatory T cell (Treg) program, at the transcriptomic and methylome levels. Accordingly, Tfr imprinting stigmata were found on FL-Tfh and FL-B cells, compared to their physiological counterparts. In addition, FL-Tfr co-culture with autologous FL-Tfh or cytotoxic FL-CD8+ T cells inhibited their proliferation in vitro. Finally, although FL-Tfr shared many characteristics with Treg, TCR sequencing analyses demonstrated that part of them derived from precursors shared with FL-Tfh. Discussion: Altogether, these findings uncover the role and origin of a Tfr subset in FL niche and may be useful for lymphomagenesis knowledge and therapeutic management.


Asunto(s)
Linfoma Folicular , Linfocitos T Reguladores , Linfoma Folicular/inmunología , Linfoma Folicular/genética , Linfoma Folicular/patología , Humanos , Linfocitos T Reguladores/inmunología , Perfilación de la Expresión Génica , Transcriptoma , Microambiente Tumoral/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Células T Auxiliares Foliculares/inmunología , Células T Auxiliares Foliculares/metabolismo , Masculino , Femenino , Técnicas de Cocultivo , Centro Germinal/inmunología
2.
Blood Adv ; 5(23): 5372-5386, 2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34555842

RESUMEN

Non-Hodgkin B-cell lymphomas (B-NHL) mainly develop within lymph nodes as aggregates of tumor cells densely packed with their surrounding microenvironment, creating a tumor niche specific to each lymphoma subtypes. In vitro preclinical models mimicking biomechanical forces, cellular microenvironment, and 3D organization of B-cell lymphomas remain scarce, while all these parameters are key determinants of lymphomagenesis and drug resistance. Using a microfluidic method based on cell encapsulation inside permeable, elastic, and hollow alginate microspheres, we developed a new tunable 3D model incorporating lymphoma B cells, extracellular matrix (ECM), and/or tonsil stromal cells (TSC). Under 3D confinement, lymphoma B cells were able to form cohesive spheroids resulting from overexpression of ECM components. Moreover, lymphoma B cells and TSC dynamically formed self-organized 3D spheroids favoring tumor cell growth. 3D culture induced resistance to the classical chemotherapeutic agent doxorubicin, but not to the BCL2 inhibitor ABT-199, identifying this approach as a relevant in vitro model to assess the activity of therapeutic agents in B-NHL. RNA-sequence analysis highlighted the synergy of 3D, ECM, and TSC in upregulating similar pathways in malignant B cells in vitro than those overexpressed in primary lymphoma B cells in situ. Finally, our 3D model including ECM and TSC allowed long-term in vitro survival of primary follicular lymphoma B cells. In conclusion, we propose a new high-throughput 3D model mimicking lymphoma tumor niche and making it possible to study the dynamic relationship between lymphoma B cells and their microenvironment and to screen new anti-cancer drugs.


Asunto(s)
Antineoplásicos , Linfoma de Células B , Linfoma no Hodgkin , Linfocitos B , Proliferación Celular , Humanos , Linfoma de Células B/tratamiento farmacológico , Microambiente Tumoral
3.
Front Immunol ; 11: 559866, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33133070

RESUMEN

Fibroblastic reticular cells (FRCs) are the specialized lymphoid stromal cells initially identified as triggering T-cell recruitment and dynamic motion in secondary lymphoid organs. Interestingly, FRCs also display antigen presentation capacities and support lymphocyte survival. CXCR5+CD4+ follicular T cells are important players of B-cell maturation and antibody response. Our study reported that in vitro-differentiated FRC-like cells enhanced the growth of the whole CXCR5+CD4+ T-cell compartment, while enhancing IL-4 secretion specifically by the PD1dimCXCR5+CD4+ cell subset, in a Notch- and ICAM1/LFA1-dependent manner. In addition, we revealed that in follicular lymphoma (FL) tissues, previously identified as enriched for PD1hiCXCR5hiCD4+ mature follicular helper T cells, PD1dimCXCR5+CD4+ T cells displayed an enrichment for Notch and integrin gene signatures, and a Notch and ICAM-1-dependent overexpression of IL-4 compared to their non-malignant counterparts. These findings suggest that the crosstalk between FRCs and CXCR5+PD1dimCD4+ T cells may contribute to the FL IL-4 rich environment, thus providing new insights in FL lymphomagenesis.


Asunto(s)
Interleucina-4/biosíntesis , Activación de Linfocitos/inmunología , Tejido Linfoide/citología , Tejido Linfoide/fisiología , Células del Estroma/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Biomarcadores , Comunicación Celular , Proliferación Celular , Supervivencia Celular , Citocinas/biosíntesis , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Molécula 1 de Adhesión Intercelular/metabolismo , Activación de Linfocitos/genética , Receptores CXCR5/metabolismo , Receptores Notch/metabolismo , Transcriptoma
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