Extrafollicular CD4+ T-B interactions are sufficient for inducing autoimmune-like chronic graft-versus-host disease

Deng, Ruishu; Hurtz, Christian; Song, Qingxiao; Yue, Chanyu; Xiao, Gang; Yu, Hua; Wu, Xiwei; Müschen, Markus; Forman, Stephen J.; Martin, Paul J.; Zeng, Defu

doi:10.1038/s41467-017-00880-2

Cited by 57 publications

(85 citation statements)

References 71 publications

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“…GVL models, cGVHD models, T-cell purification, and T-cell depleted bone marrow, antibodies and flow cytometry, in vitro T-cell polarization, in vitro and in vivo mixed lymphocyte reactions, in vitro and in vivo iTreg stability assay, lymphocyte isolation from recipient liver, histological analysis, DNA methylation assay, human Sirt-1 activity assay, and western blotting analysis are described in previously published work [20][21][22][23][24][25][26][27] and are also detailed in the supplemental Methods, available on the Blood Web site.…”

Section: Methodsmentioning

confidence: 99%

Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice

Daenthanasanmak¹,

Iamsawat²,

Chakraborty

et al. 2019

Blood

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K E Y P O I N T S l Deficiency of Sirt-1 reduces T-cell pathogenicity in GVHD by enhancing p53 acetylation in T cells and promoting iTreg stability. l Treatment with a Sirt-1 inhibitor reduces Tfh generation, B-cell activation, and plasma cell differentiation during cGVHD development.Graft-versus-host disease (GVHD) remains one of the major complications after allogeneic bone marrow transplantation (allo-BMT). Sirtuin-1 (Sirt-1) plays a crucial role in various biological processes including cellular senescence, metabolism, and inflammatory responses. Sirt-1 deacetylation regulates different transcription factors that are important for modulating immune responses. In the current study, we addressed the role of Sirt-1 in GVHD induction by employing Sirt-1 conditional knockout mice as well as a pharmacological Sirt-1 inhibitor. Using major histocompatibility complex (MHC)-mismatched and MHC-matched murine BMT models, we found that Sirt-1 2/2 T cells had a reduced ability to induce acute GVHD (aGVHD) via enhanced p53 acetylation. Sirt-1-deficient T cells also promoted induced regulatory T cell (iTreg) differentiation and inhibited interferon-g production after allo-BMT. Sirt-1 deletion in iTregs increased Foxp3 stability and restrained iTreg conversion into pathogenic T cells. Furthermore, we found that administration with a Sirt-1 inhibitor, Ex-527, significantly improved recipient survival and clinical scores, with no signs of tumor relapse. These results indicate that Sirt-1 inhibition can attenuate GVHD while preserving the graft-versus-leukemia effect. Consistently, Sirt-1-deficient T cells also displayed a remarkably reduced ability to induce chronic GVHD (cGVHD). Mechanistic studies revealed that Sirt-1 deficiency in T cells enhanced splenic B-cell reconstitution and reduced follicular T helper cell development. Sirt-1 deficiency in T cells modulated donor B-cell responses reducing both B-cell activation and plasma cell differentiation. In addition, therapeutic Sirt-1 inhibition could both prevent cGVHD and reduce established cGVHD. In conclusion, Sirt-1 is a promising therapeutic target for the control of aGVHD and cGVHD pathogenesis and possesses high potential for clinical application. (Blood. 2019;133 (3):266-279) Graft-versus-host disease (GVHD) remains one of the major complications after allogeneic bone marrow transplantation (allo-BMT). Acute GVHD (aGVHD) is distinguished by uncontrolled activation, migration, and proliferation of allogeneic donor T cells, as well as their production of pro-inflammatory 266 blood®

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Section: Methodsmentioning

confidence: 99%

Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice

Daenthanasanmak¹,

Iamsawat²,

Chakraborty

et al. 2019

Blood

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“…58 T FH are a T-cell subset that has recently been shown to be correlated with cGVHD pathogenesis. 32,34 Although the role of T FH and GC B cells in murine models of cGVHD is still under debate, 29,59 Forcade et al recently indicated a key role of T FH , which strongly correlated with cGVHD in human patients. 33 Accordingly, in our study murine recipients of XBP-1 KO B cells displayed an indirect impact on T FH cell differentiation, where donor T FH cells were reduced in the spleens.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

Schutt

Tang

et al. 2018

Blood Advances

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Key Points• Targeting XBP-1 on B cells is sufficient to prevent cGVHD.• Pharmacologic inhibition of IRE-1a/ XBP-1 prevents cGVHD while preserving GVL activity. which correlated with reductions in donor T-cell and dendritic cell skin infiltrates. Inhibition of the IRE-1a/XBP-1 pathway also preserved the GVL effect against chronic myelogenous leukemia mediated by allogeneic splenocytes. Collectively, the ER stress response mediated by the IRE-1a/XBP-1 axis is required for cGVHD development but dispensable for GVL activity.

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“…A major role for EF reactions in the generation of pathogenic autoreactive B cells has also been established in other mouse models, including the NZB/W and graft-vs-host models of lupus-like autoimmunity. 59,60 It is important to note that, concordant with human SLE factors, murine lupus can be induced by dysregulation of pathways Other studies, however, suggest that the defining ABC transcription…”

Section: E X Tr Afollicul Ar B-cell Re Ac Ti On S In S Le Model Smentioning

confidence: 99%

Extrafollicular responses in humans and SLE

Jenks

Cashman

Woodruff

et al. 2019

Immunological Reviews

222

197

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Summary Chronic autoimmune diseases, and in particular Systemic Lupus Erythematosus (SLE), are endowed with a long‐standing autoreactive B‐cell compartment that is presumed to reactivate periodically leading to the generation of new bursts of pathogenic antibody‐secreting cells (ASC). Moreover, pathogenic autoantibodies are typically characterized by a high load of somatic hypermutation and in some cases are highly stable even in the context of prolonged B‐cell depletion. Long‐lived, highly mutated antibodies are typically generated through T‐cell–dependent germinal center (GC) reactions. Accordingly, an important role for GC reactions in the generation of pathogenic autoreactivity has been postulated in SLE. Nevertheless, pathogenic autoantibodies and autoimmune disease can be generated through B‐cell extrafollicular (EF) reactions in multiple mouse models and human SLE flares are characterized by the expansion of naive‐derived activated effector B cells of extrafollicular phenotype. In this review, we will discuss the properties of the EF B‐cell pathway, its relationship to other effector B‐cell populations, its role in autoimmune diseases, and its contribution to human SLE. Furthermore, we discuss the relationship of EF B cells with Age‐Associated B cells (ABCs), a TLR‐7‐driven B‐cell population that mediates murine autoimmune and antiviral responses.

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Extrafollicular CD4+ T-B interactions are sufficient for inducing autoimmune-like chronic graft-versus-host disease

Cited by 57 publications

References 71 publications

Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice

Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

Extrafollicular responses in humans and SLE

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