Cutting Edge: In the Absence of Regulatory T Cells, a Unique Th Cell Population Expands and Leads to a Loss of B Cell Anergy

Leonardo, Steven; Santis, Jessica L. De; Malherbe, Laurent; Gauld, Stephen B.

doi:10.4049/jimmunol.1103731

Cited by 13 publications

(16 citation statements)

References 21 publications

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“…A regulatory role for CD4 + CD25 + T cells on B cells is still a matter of debate. In a mouse model of autoimmunity, depletion of Treg cells leads to loss of anergy in B cells and the production of autoantibodies [24]. We never observed an increase of Treg cells in our culture conditions.…”

Section: Inhibition Of B-cell Function By Mscs In Hdsmentioning

confidence: 58%

Inhibition of B-Cell Proliferation and Antibody Production by Mesenchymal Stromal Cells Is Mediated by T Cells

Rosado

Bernardo

Scarsella

et al. 2015

Stem Cells and Development

140

105

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Bone marrow (BM)-derived mesenchymal stromal cells (MSCs), endowed with immunosuppressive and antiinflammatory properties, represent a promising tool in immunoregulatory and regenerative cell therapy. Clarifying the interactions between MSCs and B-lymphocytes may be crucial for designing innovative MSC-based strategies in conditions in which B cells play a role, including systemic lupus erythematosus (SLE) and rejection of kidney transplantation. In this study, we show that, both in healthy subjects and in patients, in vitro B-cell proliferation, plasma-cell differentiation, and antibody production are inhibited by BM-derived MSCs when peripheral blood lymphocytes are stimulated with CpG, but not when sorted B cells are cultured with MSCs + CpG. Inhibition is restored in CpG + MSC cocultures when sorted T cells are added to sorted B cells, suggesting that this effect is mediated by T cells, with both CD4 + and CD8 + cells playing a role. Moreover, cell-cell contact between MSCs and T cells, but not between MSCs and B cells, is necessary to inhibit B-cell proliferation. Thus, the presence of functional T cells, as well as cell-cell contact between MSCs and T cells, are crucial for B-cell inhibition. This information can be relevant for implementing MSC-based therapeutic immune modulation in patients in whom T-cell function is impaired.

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Section: Inhibition Of B-cell Function By Mscs In Hdsmentioning

confidence: 58%

Inhibition of B-Cell Proliferation and Antibody Production by Mesenchymal Stromal Cells Is Mediated by T Cells

Rosado

Bernardo

Scarsella

et al. 2015

Stem Cells and Development

140

105

View full text Add to dashboard Cite

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“…Co‐cultures were performed using a previously described method . Briefly, CD4 + T‐cell subsets (non‐Tfh, Tfh) were isolated by flow cytometric cell sorting (non‐Tfh cells: CD4 + Foxp3 − CXCR5 − PD‐1 − , Tfh cells: CD4 + Foxp3 − CXCR5 + PD‐1 + ).…”

Section: Methodsmentioning

confidence: 99%

Modulation of B‐cell tolerance by Murine Gammaherpesvirus 68 infection: requirement for Orf73 viral gene expression and follicular helper T cells

et al. 2013

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SummaryViruses such as Epstein-Barr virus (EBV) have been linked to mechanisms that support autoantibody production in diseases such as systemic lupus erythematosus. However, the mechanisms by which viruses contribute to autoantibody production remain poorly defined. This stems in part, from the high level of seropositivity for EBV (> 95%) and the exquisite species specificity of EBV. In this study we overcame these problems by using murine gammaherpesvirus 68 (MHV68), a virus genetically and biologically related to EBV. We first showed that MHV68 drives autoantibody production by promoting a loss of B-cell anergy. We next showed that MHV68 infection resulted in the expansion of follicular helper T (Tfh) cells in vivo, and that these Tfh cells supported autoantibody production and a loss of B-cell anergy. Finally, we showed that the expansion of Tfh cells and autoantibody production was dependent on the establishment of viral latency and expression of a functional viral gene called Orf73. Collectively, our studies highlighted an unexpected role for viral latency in the development of autoantibodies following MHV68 infection and suggest that virus-induced expansion of Tfh cells probably plays a key role in the loss of B-cell anergy.

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“…We have previously shown that B-and T-cell zones are significantly altered in Foxp3-deficient mice [3]. DT treatment of Foxp3 DTR mice for 12 days results in a mild phenotype but is associated with the presence of GL7-expressing non-B cells outside, and within, remaining B-cell zones [31]. We predict these are helper T cells as our studies indicate only CD4 + T cells and B cells express GL7 in the absence of Treg cells [31].…”

Section: Discussionmentioning

confidence: 99%

“…DT treatment of Foxp3 DTR mice for 12 days results in a mild phenotype but is associated with the presence of GL7-expressing non-B cells outside, and within, remaining B-cell zones [31]. We predict these are helper T cells as our studies indicate only CD4 + T cells and B cells express GL7 in the absence of Treg cells [31]. Therefore, the presence of GL7-expressing T cells outside of B-cell zones may help promote autoimmunity by being available to B cells excluded from follicular areas.…”

Section: Discussionmentioning

confidence: 99%

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

et al. 2012

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The maintenance of B-cell anergy is essential to prevent the production of autoantibodies and autoimmunity. However, B-cell extrinsic mechanisms that regulate B-cell anergy remain poorly understood. We previously demonstrated that regulatory T (Treg) cells are necessary for the maintenance of B-cell anergy. We now show that in Treg-cell-deficient mice, helper T cells are necessary and sufficient for loss of B-cell tolerance/anergy. In addition, we show that the absence of Treg cells is associated with an increase in the proportion of CD4 + cells that express GL7 and correlated with an increase in germinal center follicular helper T (GC-T FH ) cells. These GC-T FH cells, but not those from Tregcell-sufficient hosts, were sufficient to drive antibody production by anergic B cells. We propose that a function of Treg cells is to prevent the expansion of T FH cells, especially GC-T FH cells, which support autoantibody production.Keywords: anergy r autoimmunity r B cells r T FH r Treg cells Supporting Information available online IntroductionThe production of autoantibodies due to loss of B-cell tolerance is central to the development of autoimmunity. Our understanding of the mechanisms that maintain B-cell tolerance, especially B-cell anergy, remains poorly defined. The absence of regulatory T (Treg) cells results in the development of IPEX, a fatal disease associated with the development of significant autoantibodies and autoimmunity [1,2]. The development of autoantibodies suggests that Treg cells play a key role in regulating B-cell tolerance, a statement supported by our previous study showing a role for Treg cells in the maintenance of B-cell anergy [3].Numerous signaling molecules have been identified whose absence prevents the establishment or maintenance of B-cell Correspondence: Dr. Stephen B. Gauld e-mail: sgauld@mcw.edu anergy at the intrinsic level (reviewed in [4]). However, our understanding of B-cell extrinsic mechanisms that regulate B-cell anergy remains poor. DCs have been shown to both positively and negatively regulate autoantibody production [5][6][7]. Helper T cells, or signals associated with T-cell help, appear to negatively regulate B-cell tolerance [8][9][10][11][12]. It remains unclear as to which helper T-cell populations can support autoantibody production.Follicular helper T (T FH ) cells are defined based on their expression of the chemokine receptor CXCR5, the transcription factor Bcl6, and play an essential role in providing help to B cells, promoting antibody production [13][14][15]. However, a role for T FH cells in the production of autoantibodies is less well defined. The expansion of T FH cells is known to be associated with a lupus-like disease in sanroque mice and CD4 + cells from the sanroque model support antichromatin autoantibody production in an adoptive transfer system [16,17]. A study by Simpson et al. [18] In our study, we use the Foxp3 DTR mouse model [20] to deplete the complete Treg-cell population in adult hosts and show that Treg cells are essential to prevent th...

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Cutting Edge: In the Absence of Regulatory T Cells, a Unique Th Cell Population Expands and Leads to a Loss of B Cell Anergy

Cited by 13 publications

References 21 publications

Inhibition of B-Cell Proliferation and Antibody Production by Mesenchymal Stromal Cells Is Mediated by T Cells

Inhibition of B-Cell Proliferation and Antibody Production by Mesenchymal Stromal Cells Is Mediated by T Cells

Modulation of B‐cell tolerance by Murine Gammaherpesvirus 68 infection: requirement for Orf73 viral gene expression and follicular helper T cells

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

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