Peritoneal Cavity Regulatory B Cells (B10 Cells) Modulate IFN-γ+CD4+ T Cell Numbers during Colitis Development in Mice

Abstract We have established two mouse models of chronic graft versus host disease (cGVHD): one is an MHC-matched DBA/2 donor to BALB/c recipient, and this model amplifies the role of CD4+ T and B cells in transplants; the other model is an MHC-mismatched C57BL/6 donor to BALB/c recipient, and this model amplifies the role of de novo-developed CD4+ T and B cells. BALB/c recipients in both models started to develop scleroderma ~35 days after transplantation of donor spleen and bone marrow cells and this peaked ~50 days after transplantation. BALB/c recipients given DBA/2 transplants also developed proteinuria due to IgG anti-dsDNA autoantibody deposition in the glomeruli. We have reported that donor CD4+ T and B cells play critical roles in the pathogenesis of chronic GVHD (J. Immunol 2012 and 2013). Administration by I.V. injection of depleting anti-CD20 prevented induction of chronic GVHD in both models (Biol. Blood and Marrow Transplant 2014). In the current studies, using these two models, we tested whether oral administration of Ibrutinib could prevent induction of cGVHD. Ibrutinib was gavaged at 12.5 mg/kg/day from day 0 to day 30 or given in drinking water at 35 mg/kg/day (0.16 mg/ml) from day 0 to day 50. We found that administration of Ibrutinib significantly delayed the onset of proteinuria in the model of DBA/2 donor to BALB/c recipient, but accelerated the onset and increased the severity of scleroderma in 20/20 recipients given DBA/2 transplants and 9/9 recipients given C57BL/6 transplants as measured by a clinical score system. Administration of Ibrutinib significantly reduced CD138+B220lo plasma cells but not CD138-B220+ B cells in the spleen and peripheral lymph nodes of both recipients. Administration of Ibrutinib slightly reduced CD4+ T cell numbers in the spleen but significantly increased CD4+ T cell numbers in the peripheral lymph nodes, although there was no significant impact on CD4+ T cell expression of IFN-g and TNF-α in both recipients. These results indicate that, although oral administration of Ibrutinib is able to reduce B cell activation and differentiation into plasma cells, it is ineffective at inhibiting the CD4+ T cell expansion that mediates scleroderma in the models of DBA/2 donor to MHC-matched BALB/c recipient and C57BL/6 donor to MHC-mismatched BALB/c recipient. Our result is in contrast to a previous report showing that oral administration of Ibrutinib prevented induction of chronic GVHD with bronchiolitis obliterans in a mouse model and reversed scleroderma in another mouse model (Poster 2591, AACR 2014, San Diego). Further discussion about the differences is warranted. (This work was supported by Nesvig Lymphoma Foundation). Disclosures No relevant conflicts of interest to declare.

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Effector and regulatory B cells: modulators of CD4+ T cell immunity

Nature Reviews Immunology ◽

10.1038/nri2729 ◽

2010 ◽

Vol 10 (4) ◽

pp. 236-247 ◽

Cited By ~ 400

Author(s):

Frances E. Lund ◽

Troy D. Randall

Keyword(s):

T Cell ◽

B Cells ◽

T Cell Immunity ◽

Cd4 T Cell ◽

Regulatory B Cells ◽

Cell Immunity

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Dysfunctional Tregs with Absence of Cytokine-Secreting CD4+ T-Cell Subsets and Marked Expansion of Th1 Cells Is a Hallmark of Idiopathic Aplastic Anaemia (AA)

Blood ◽

10.1182/blood.v116.21.2233.2233 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2233-2233

Author(s):

Shahram Kordasti ◽

Judith C. W. Marsh ◽

Pilar Perez Abellan ◽

Sufyan Alkhan ◽

Janet Hayden ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Cd4 T Cells ◽

Cytokine Secretion ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Th1 Cells ◽

Healthy Controls ◽

Ifn Γ

Abstract Abstract 2233 Introduction: Autoimmunity is an important contributor in the aetiology of AA. Although the expansion of oligoclonal CD8+ T-cells and their correlation with response to immunosuppressive therapy (IST) has been reported previously, the role of CD4+ in the pathogenesis is not elucidated. The focus of this study was to investigate the role of different CD4+ T-cell subsets, including regulatory T-cells (Tregs) and T helpers (Th1, Th2 and Th17) in the pathobiology of idiopathic AA. Patients and Methods: The percentage and absolute numbers of CD4+ and CD8+ T-cell subsets, NK & B cells and dendritic cells (DCs) in peripheral blood were assessed in 42 patients with idiopathic AA prior to any IST and 8 healthy age matched controls. T-cells were stimulated first and stained intracellularly for IFN-γ and TNF-a (Th1), IL-4 (Th2) and IL-17 (Th17). Serum levels of 30 cytokines were measured by 30 Plex bead analysis (Luminex). NK cells were defined as CD3– CD56+. B cells were defined as CD3-CD19+. CD3+ CD4+.T-cell subsets were defined as CD45RO–CD27+ naïve, CD45RO+ CD27+ CD62L+ central memory, CD45RO+ CD27+ CD62L– effector memory, CD45RO+CD27– effectors and CD45RO– CD27– terminal effectors. DCs were defined based on their BDCA 1,2, 3 & CD16 expression. CD4 Tregs were defined as CD3+CD4+ CD25high CD27+Foxp3+. Treg subsets were defined as (1) CD45RA+CD25lo resting Tregs, (2) CD45RA-CD25hi activated Tregs, and (3) cytokine-secreting CD45RA-CD25lo non-Tregs1. Treg function was evaluated by cytokine secretion of T effector cells (Te) with and without Tregs. IFN-γ secreting CD4+ T-cells (Th1) were enriched by magnetic beads followed by FACS sorting. The clonality of Th1 cells was evaluated based on the diversity of T-cell receptors by spectratyping as well as sequencing. Transcription factor expression was measured by qPCR. Results: There were no significant differences in the number or percentage of different CD8 T-cells compared to healthy controls. Surprisingly, despite a borderline decrease in the absolute number of naïve (p=0.19) and central memory (p=0.20) CD4+T-cells the number and percentage of Tregs were no different from healthy controls (1.36×107/L v 1.34×107/L, p=0.57). Although the ratio of Tregs to CD4+ T-effectors (Te) was higher than in healthy controls, the difference was not significant (0.49 v 0.12, p=0.86). The absolute numbers and percentages of Th1 cells and TNF-α + CD4+ T-cells were significantly higher in AA patients compared to healthy controls (4.2 × 107/L v 0.9 × 107/L & 2.44 × 108 v 1.26 × 108(p=0.001, p=0.004)). The diversity of T-cell receptor on Th1 cells was significantly lower compared to healthy age matched controls (on average 21 & 52 peaks). Amongst AA patients, the numbers of Th2, Th17, NK and B cells were not significantly different from healthy controls, whereas the absolute numbers of all DCs were reduced(p<0.01). The serum levels of proliferative cytokines, EGF (p=0.01), HGF (p=0.01), VEGF (p=0.01) and pro-inflammatory cytokines IL-13 (p=0.02), IL-8 (p<0.001) were significantly higher in AA patients. The percentage of cytokine secreting CD4+ CD25+ T-cells was markedly decreased in AA patients and the activated Treg subsets were predominantly of CD45RA+ phenotype, which was significantly different from healthy controls. Sorted Tregs from AA patients were unable to suppress cytokine secretion by Te cells in a 1:1 co-culture. However, IL-2, IFN-γ and TNF-α secretion of Te from AA patients was suppressible by allogeneic Tregs from healthy controls (on average 11 time suppression), whereas Tregs from AA patients were unable to suppress healthy Te cells. However, dysfunctional Tregs were not associated with abnormality of transcription factors, as judged by the levels of STAT1, 3, 4, 5 & 6, FoxP3 & T-bet of Tregs that were not significantly different from healthy age matched controls. Conclusion: Our data show that although FoxP3+ Tregs are normal in AA, a subset of these cells is markedly reduced and the activated Tregs aberrantly express CD45RA. Furthermore, unlike normal Tregs, the Tregs from AA patients do not suppress the inflammatory cytokine secretion by Te cells. The absence of DCs in the peripheral blood suggests their immigration to the inflammation site (e.g. bone marrow), which may play a role in the polarisation of T helpers toward a Th1 phenotype. Clonal expansion of Th1 cells may suggest potential antigen specificity that may lead to AA phenotype. 1. Miyara M, et al. Immunity. 2009. Disclosures: No relevant conflicts of interest to declare.

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CD4+T Cell–Derived IL-21 and Deprivation of CD40 Signaling Favor the In Vivo Development of Granzyme B–Expressing Regulatory B Cells in HIV Patients

The Journal of Immunology ◽

10.4049/jimmunol.1402568 ◽

2015 ◽

Vol 194 (8) ◽

pp. 3768-3777 ◽

Cited By ~ 31

Author(s):

Christof Kaltenmeier ◽

Ali Gawanbacht ◽

Thamara Beyer ◽

Stefanie Lindner ◽

Timo Trzaska ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Granzyme B ◽

Cd4 T Cell ◽

Regulatory B Cells ◽

Hiv Patients

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B Cell Presentation of Chlamydia Antigen Selects Out Protective CD4γ13 T Cells: Implications for Genital Tract Tissue-Resident Memory Lymphocyte Clusters

Infection and Immunity ◽

10.1128/iai.00614-17 ◽

2017 ◽

Vol 86 (2) ◽

Cited By ~ 9

Author(s):

Raymond M. Johnson ◽

Hong Yu ◽

Norma Olivares Strank ◽

Karuna Karunakaran ◽

Ying Zhu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Genital Tract ◽

Cell Subset ◽

Cd4 T Cell ◽

Content Type ◽

T Cell Subset ◽

Ifn Γ

ABSTRACTSurveillance and defense of the enormous mucosal interface with the nonsterile world are critical to protecting the host from a wide range of pathogens.Chlamydia trachomatisis an intracellular bacterial pathogen that replicates almost exclusively in the epithelium of the reproductive tract. The fallopian tubes and vagina are poorly suited to surveillance and defense, with limited immune infrastructure positioned near the epithelium. However, a dynamic process during clearing primary infections leaves behind new lymphoid clusters immediately beneath the epithelium. These memory lymphocyte clusters (MLCs) harboring tissue-resident memory (Trm) T cells are presumed to play an important role in protection from subsequent infections. Histologically, humanChlamydiaMLCs have prominent B cell populations. We investigated the status of genital tract B cells duringC. muridaruminfections and the nature of T cells recovered from immune mice using immune B cells as antigen-presenting cells (APCs). These studies revealed a genital tract plasma B cell population and a novel genital tract CD4 T cell subset producing both gamma interferon (IFN-γ) and interleukin-13 (IL-13). A panel of CD4 T cell clones and microarray analysis showed that the molecular fingerprint of CD4γ13 T cells includes a Trm-like transcriptome. Adoptive transfer of aChlamydia-specific CD4γ13 T cell clone completely prevented oviduct immunopathology without accelerating bacterial clearance. Existence of a CD4γ13 T cell subset provides a plausible explanation for the observation that human peripheral blood mononuclear cell (PBMC)Chlamydia-specific IFN-γ and IL-13 responses predict resistance to reinfection.

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Faculty Opinions recommendation of Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717961005.793467906 ◽

2012 ◽

Author(s):

Kazuhiko Yamamoto ◽

Keishi Fujio

Keyword(s):

T Cell ◽

B Cells ◽

Regulatory B Cells

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The Effect of Antiretroviral Therapy on IL-6, IL-1β, TNF-α, IFN-γ Levels and their Relationship with HIV-RNA and CD4+ T Cells in HIV Patients

Current HIV Research ◽

10.2174/1570162x18666200712174642 ◽

2020 ◽

Vol 18 (5) ◽

pp. 354-361

Author(s):

Gülay Okay ◽

Meliha Meric Koc ◽

Eray Metin Guler ◽

Ayşegül Yabaci ◽

Abdürrahim Kocyigit ◽

...

Keyword(s):

T Cell ◽

Hiv Infection ◽

Cell Count ◽

Cd4 T Cell ◽

Positive Correlation ◽

Hiv Rna ◽

Tnf Α ◽

Cytokine Levels ◽

Ifn Γ ◽

Cd4 T Cell Count

Background: Serum cytokine levels over the course of HIV infection usually increase with immunosuppression and decrease after antiretroviral treatment (ART). Objectives: The aim of the study is to compare cytokine levels between HIV-infected patients (HIP) and controls and investigate the relationship between CD4+T cell count, HIV-RNA levels, and cytokine levels. Methods: The study subjects comprised ART-naive HIP (n=30) with no comorbidities and age-and sex-matched healthy controls. We measured levels of IL-6, IL-1β, TNF-α, and IFN-γ in serum samples of HIP at the beginning and at month 6 of ART and in controls. Results: The mean age of the study subjects was 38.7 ±10.3 years, with men making up 86.7% of the study subjects (n=26). IL-6, IL-1β, and TNF-α levels were significantly higher in both ART-naive (p<0.001, p=0.002, p=0.001) and ART-experienced HIP (p<0.001) than controls. The IFN-γ level was lower in both ART-naive and ART-experienced HIP compared to controls (p=0.082 and p=0.002). There was a positive correlation between the CD4+T cell count and serum concentration of IFN- γ(r=0.320, p<0.05). While the serum IFN-γ concentration showed a negative correlation with the HIVRNA level(r=-0.412, p<0.001), the serum IL-1β, IL-6, and TNF-α concentrations showed a positive correlation with the HIV-RNA level (r=0.349, p<0.001; r:0.54, p<0.001; r:0.438, p<0.00). Conclusions: Although serum concentrations of IL-6, IL-1β and TNF-α showed a significant decrease after ART, they were still significantly higher than the controls. IFN-γ responded differently to ART compared to the other cytokines, indicating that it may play a distinct and important role in the pathogenesis of HIV infection.

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