Mechanisms by Which B Cells and Regulatory T Cells Influence Development of Murine Organ-Specific Autoimmune Diseases

Ellis, Jason S.; Braley‐Mullen, Helen

doi:10.3390/jcm6020013

Cited by 18 publications

(10 citation statements)

References 120 publications

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“…However, given the observed prognostic interaction between T cells and B cells, future studies should also explore whether such an interaction exists in the predictive setting, and how neoadjuvant chemo- or chemoradiotherapy affects the density and prognostic effects of various subsets of TILs. In addition, the role of B cells in immune checkpoint inhibitor therapy has not yet been fully examined and may be of importance, since it has lately been shown that also T cells can be dependent on B cell activation [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma

Svensson

Warfvinge²,

Fristedt³

et al. 2017

Oncotarget

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BackgroundSeveral studies have demonstrated a prognostic impact of tumor-infiltrating T lymphocytes and natural killer (NK) cells in esophageal and gastric adenocarcinoma, but whether these associations differ by the density of tumor-infiltrating immune cells of the B cell lineage remains largely unknown.ResultsHigh infiltration of any T and NK lymphocytes investigated was in general associated with a favorable prognosis, but the strongest beneficial prognostic impact was seen in combination with high B lymphocyte infiltration. These findings were most evident in gastric cancer, where significant interactions in relation to OS were observed for CD3+, CD8+ and FoxP3+ with CD20+ cells (pinteraction =0.012, 0.009 and 0.007, respectively) and for FoxP3+ with IGKC+ cells (pinteraction =0.034). In esophageal tumors, there was only a significant interaction for CD3+ and CD20 + cells (pinteraction =0.028).MethodsImmunohistochemistry and automated image analysis was applied to assess the density of T lymphocytes (CD3+, CD8+, FoxP3+) and NK cells (NKp46+) in chemoradiotherapy-naïve tumors from a consecutive cohort of 174 patients with resected esophageal or gastric adenocarcinoma. The density of B lymphocytes (CD20+) and plasma cells (IGKC+) had been assessed previously. Kaplan-Meier analysis and Cox proportional hazard's modelling was applied to examine the impact of the investigated markers on time to recurrence (TTR) and overall survival (OS).ConclusionsThese data support that the antitumoral effects of tumor-infiltrating T lymphocytes in esophageal and gastric adenocarcinoma may be largely dependent on a functional interplay between T and B lymphocytes or plasma cells.

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Section: Discussionmentioning

confidence: 99%

The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma

Svensson

Warfvinge²,

Fristedt³

et al. 2017

Oncotarget

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“…However, in PD-1 −/− mice, activation of autoreactive T and B cells is apparently not diminished, because autoimmunity and autoantibody responses are increased after anti-CD40L, even though GCs are effectively depleted. B cells function as important APCs for the development of ATD and pSS (59), suggesting that anti-CD40L does not effectively inhibit T cell/APC and/or B cell activation in PD-1 −/− mice. Effective inhibition by anti-CD40L apparently requires an intact PD-1/PDL pathway, as shown for CD28 −/− mice given anti–PD-1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways

Voynova¹,

Mahmoud²,

Woods

et al. 2018

ImmunoHorizons

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CD40/CD40L interactions play a critical role in immunity and autoimmunity. In this study, we sought to understand the requirement for CD40 signaling in the programmed cell death-1 (PD-1) checkpoint and CD28 costimulatory pathways important for maintenance of peripheral tolerance. Blocking either pathway can result in loss of self-tolerance and development of autoimmunity. We found that primary Sjögren’s syndrome (pSS) and autoimmune thyroid diseases (ATDs) that develop spontaneously in CD28-deficient IFN-γ −/− NOD.H-2h4 (CD28 −/− ) mice required CD40 signaling. Specifically, blockade of CD40L with the anti-CD40L mAb, MR1, inhibited autoantibody production and inflammation in thyroid and salivary gland target tissues. Unexpectedly, however, ATD and pSS in PD-1–deficient IFN-γ −/− NOD.H-2h4 (PD-1 −/− ) mice developed independently of CD40/CD40L interactions. Treatment with MR1 had no effect and even exacerbated disease development in pSS and ATD, respectively. Most interesting, anti-thyroglobulin and pSS-associated autoantibodies were increased following anti-CD40L treatment, even though MR1 effectively inhibited the spontaneous splenic germinal centers that form in PD-1–deficient mice. Importantly, blockade of the PD-1 pathway by administration of anti–PD-1 mAb in CD28 −/− mice recapitulated the PD-1 −/− phenotype, significantly impacting the ability of MR1 to suppress ATD and pSS in these mice. These results indicate that there can be different pathways and requirements to autoimmune pathogenesis depending on the availability of specific checkpoint and costimulatory receptors, and an intact PD-1 pathway is apparently required for inhibition of autoimmunity by anti-CD40L.

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“…Several studies have demonstrated that B cells can affect Treg responses to autoimmune diseases ( 29 – 32 ). In mouse studies using both genetically B cell-deficient and anti-CD20-treated animals, B cells have been reported to have both positive and negative effects on the size and function of the Treg subset (reviewed in references 33 and 34 ). Some of the differences in experimental outcomes can be attributed to the time during autoimmune disease when the depleting antibodies (Abs) were given, to mouse strain differences (NOD [ 33 ] and BALB/c [ 35 ] mice give results different from those given by C57BL/6 mice), and/or to whether the Tregs induced were peripherally derived or thymus derived.…”

Section: Introductionmentioning

confidence: 99%

B Cell Requirement for Robust Regulatory T Cell Responses to Friend Retrovirus Infection

Moore

Gonzaga

Mather

et al. 2017

mBio

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Regulatory T cells (Tregs) are immunosuppressive cells of the immune system that control autoimmune reactivity. Tregs also respond during immune reactions to infectious agents in order to limit immunopathological damage from potent effectors such as CD8+ cytolytic T lymphocytes. We have used the Friend virus (FV) model of retroviral infection in mice to investigate how viral infections induce Tregs. During acute FV infection, there is significant activation and expansion of thymus-derived (natural) Tregs that suppress virus-specific CD8+ T cell responses. Unlike conventional T cells, the responding Tregs are not virus specific, so the mechanisms that induce their expansion are of great interest. We now show that B cells provide essential signals for Treg expansion during FV infection. Treg responses are greatly diminished in B cell-deficient mice but can be restored by adoptive transfers of B cells at the time of infection. The feeble Treg responses in B cell-deficient mice are associated with enhanced virus-specific CD8+ T cell responses and accelerated virus control during the first 2 weeks of infection. In vitro experiments demonstrated that B cells promote Treg activation and proliferation through a glucocorticoid-induced receptor superfamily member 18 (GITR) ligand-dependent mechanism. Thus, B cells play paradoxically opposing roles during FV infection. They provide proliferative signals to immunsosuppressive Tregs, which slows early virus control, and they also produce virus-specific antibodies, which are essential for long-term virus control.

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Mechanisms by Which B Cells and Regulatory T Cells Influence Development of Murine Organ-Specific Autoimmune Diseases

Cited by 18 publications

References 120 publications

The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma

The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma

Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways

B Cell Requirement for Robust Regulatory T Cell Responses to Friend Retrovirus Infection

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