Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse

Blood ◽  
2007 ◽  
Vol 110 (5) ◽  
pp. 1519-1529 ◽  
Author(s):  
Peter Reichardt ◽  
Bastian Dornbach ◽  
Song Rong ◽  
Stefan Beissert ◽  
Faikah Gueler ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
B Cell ◽  
Dependent Manner ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Immunologic Synapse

Abstract Naive B cells are ineffective antigen-presenting cells and are considered unable to activate naive T cells. However, antigen-specific contact of these cells leads to stable cell pairs that remain associated over hours in vivo. The physiologic role of such pairs has not been evaluated. We show here that antigen-specific conjugates between naive B cells and naive T cells display a mature immunologic synapse in the contact zone that is absent in T-cell–dendritic-cell (DC) pairs. B cells induce substantial proliferation but, contrary to DCs, no loss of L-selectin in T cells. Surprisingly, while DC-triggered T cells develop into normal effector cells, B-cell stimulation over 72 hours induces regulatory T cells inhibiting priming of fresh T cells in a contact-dependent manner in vitro. In vivo, the regulatory T cells home to lymph nodes where they potently suppress immune responses such as in cutaneous hypersensitivity and ectopic allogeneic heart transplant rejection. Our finding might help to explain old observations on tolerance induction by B cells, identify the mature immunologic synapse as a central functional module of this process, and suggest the use of naive B-cell–primed regulatory T cells, “bTregs,” as a useful approach for therapeutic intervention in adverse adaptive immune responses.

A spectrum of biophysical interaction modes between T cells and different antigen-presenting cells during priming in 3-D collagen and in vivo

Blood ◽  
2004 ◽  
Vol 104 (9) ◽  
pp. 2801-2809 ◽  
Author(s):  
Matthias Gunzer ◽  
Carsten Weishaupt ◽  
Anja Hillmer ◽  
Yasmin Basoglu ◽  
Peter Friedl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Antigen Presenting Cells ◽  
Model Systems ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Antigen Presenting ◽  
Activated B Cells

Abstract For activation T cells engage antigen-presenting cells (APCs) in lymphatic tissues. The contact duration and kinetics (static versus dynamic) vary considerably in different model systems; however, it is unclear whether T cells, APCs, or the environment are responsible for the observed discrepancies. Using 3-D collagen matrices as structural scaffold, we directly compared the kinetics of T-cell engagement and activation by functionally major APC types, ie, dendritic cells (DCs) and resting or activated B cells. Resting B cells engaged T cells in long-lived (several hours), adhesive, and leukocyte function-associated antigen-1 (LFA-1)-dependent conjugates in 3-D collagen as well as in intact lymph nodes in vivo. DCs and preactivated B cells, however, supported predominantly dynamic, short-lived (minutes), and sequential contacts to T cells that were dependent on high cytoskeletal activity of the APCs but could not be inhibited by anti-LFA-1 treatment. Naive T cells were most strongly activated by DCs and activated B cells, whereas resting B cells were 100-fold less efficient to induce T-cell proliferation. Thus, in the same 3-D environment, naive T cells respond with a spectrum of different interaction modes dependent on the type and activation state of the APCs. Thereby, more dynamic interaction kinetics is positively correlated with higher T-cell priming efficiency. (Blood. 2004;104: 2801-2809)

scholarly journals B lymphocytes in vivo fail to prime naive T cells but can stimulate antigen-experienced T lymphocytes.

1993 ◽  
Vol 177 (3) ◽  
pp. 679-690 ◽  
Author(s):  
F Ronchese ◽  
B Hausmann
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Class Ii ◽  
T Cell Response ◽  
Scid Mice ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cell Responses

The ability of B cells or macrophages and dendritic cells (DC) to elicit class II-restricted T cell responses in vivo was compared using a mouse chimera model. Severe combined immunodeficient (SCID) mice (H-2d), reconstituted either with T or T+B lymphocytes from (H-2d x H-2b) donors, were immunized subcutaneously with protein antigen (Ag) to induce a class II-restricted T cell response. The frequency and major histocompatibility complex restriction of the resulting Ag-specific T cells were analyzed to establish whether B cells were necessary for the induction of class II-restricted T cell responses, and to determine the cell type on which priming had occurred. The results indicated that: (a) B cells are not necessary for the induction of a class II-restricted T cell response in vivo, as the frequencies of interleukin 2 (IL-2)- or IL-3-secreting T cells induced in the presence or absence of B cells were comparable. (b) Activation of naive T cells requires presentation of Ag on DC; Ag presented only on B cells is not sufficient to elicit a response. No H-2b-restricted, IL-3-secreting cells could in fact be detected in SCID mice reconstituted with naive (H-2d x H-2b) T cells and nonimmune or antigen-primed (H-2d x H-2b) B cells. (c) Previously primed T cells are able to be stimulated by Ag presented by both B cells and DC. H-2b-restricted, IL-3-secreting cells could in fact be readily demonstrated in SCID mice reconstituted with antigen-primed (H-2d x H-2b) T and B cells. Irrespective of whether the T cells were naive or previously activated, B cells were able to respond with an Ag-specific immunoglobulin G response, indicating that B cells were functional and able to present Ag in order to receive specific T cell help. Therefore, it appears that B cells are not necessary and do not participate in the initial priming of T cells; however, Ag presented by B cells can reactivate previously primed T cells. Taken together, these data indicate that during the course of an immune response Ag is first presented to naive T cells via DC, and only subsequently primed T cells can be stimulated by Ag presented by B cells.

Antigen-Pulsed, Interleukin-4-Treated B Cells Activate Primed T Cells In Vitro but not Naive T Cells In Vivo

1995 ◽  
Vol 42 (5) ◽  
pp. 517-523 ◽  
Author(s):  
R. GRAINGER ◽  
D. N. J. HART ◽  
J. D. WATSON ◽  
M. A. BAIRD
Keyword(s):  
T Cells ◽  
B Cells ◽  
Interleukin 4 ◽  
Naive T Cells ◽  
Naïve T Cells

scholarly journals Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut

2012 ◽  
Vol 209 (9) ◽  
pp. 1529-1535 ◽  
Author(s):  
Susan M. Schlenner ◽  
Benno Weigmann ◽  
Qingguo Ruan ◽  
Youhai Chen ◽  
Harald von Boehmer
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Transcription Initiation ◽  
Foxp3 Expression ◽  
Cell Development ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Smad3 Binding

Regulatory T cells (T reg cells) are essential for the prevention of autoimmunity throughout life. T reg cell development occurs intrathymically but a subset of T reg cells can also differentiate from naive T cells in the periphery. In vitro, Smad signaling facilitates conversion of naive T cells into T reg cells but results in unstable Foxp3 expression. The TGF-β–Smad response element in the foxp3 locus is located in the CNS1 region in close proximity to binding sites for transcription factors implicated in TCR and retinoic acid signaling. From in vitro experiments it was previously postulated that foxp3 transcription represents a hierarchical process of transcription factor binding in which Smad3 would play a central role in transcription initiation. However, in vitro conditions generate T reg cells that differ from T reg cells encountered in vivo. To address the relevance of Smad3 binding to the CNS1 enhancer in vivo, we generated mice that exclusively lack the Smad binding site (foxp3CNS1mut). We show that binding of Smad3 to the foxp3 enhancer is dispensable for T reg cell development in newborn and adult mice with the exception of the gut.

Naturally Occurring Regulatory T Cells Modulate Immune Responses Against Exogenous Factor VIII in Hemophilic Balb/c Mice but Not in C57BL/6J Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1160-1160
Author(s):  
Christina Hausl ◽  
Josenato Ilas ◽  
Christian Lubich ◽  
Rafi U. Ahmad ◽  
Eva M. Muchitsch ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Factor Viii ◽  
Matched Control ◽  
Antibody Responses ◽  
Protein Antigens ◽  
Naturally Occurring

Abstract Antibody responses against factor VIII (FVIII) are the major complication that arises when patients with hemophilia A are treated with factor VIII products. Therefore, understanding regulation of anti-FVIII immune responses is of outmost importance. Antibody responses are well established to result from differentiation of B cells into antibody-secreting plasma cells. B cells need help from activated CD4+ T cells to develop high-affinity antibody responses against protein antigens such as FVIII. Recently, naturally occurring CD4+CD25+ regulatory T cells have been shown to modulate antibody responses by either suppressing the function of CD4+ T helper cells or by directly acting on B cells. However, the potential importance of CD4+CD25+ T cells in regulating antibody responses to foreign protein antigens is controversial. Furthermore, the extent to which naturally occurring CD4+CD25+ T cells regulate antibody responses against exogenous proteins such as FVIII when these proteins are given to previously untreated patients is unclear. To obtain information on how important naturally occurring CD4+CD25+ T cells are under such conditions, we asked whether these cells regulate anti-FVIII antibody responses in murine hemophilia A. We studied E17 hemophilic mice with two different genetic backgrounds (C57BL/6J and Balb/c) and treated them with four intravenous doses of human FVIII given at weekly intervals. Before the first dose of FVIII, CD4+CD25+ T cells were depleted in vivo using an anti-CD25 antibody that has been shown to deplete naturally occurring CD4+CD25+ T cells in mice. In vivo depletion of regulatory T cells using the same antibody has been successfully applied in a variety of mouse studies to evaluate the significance of naturally occurring CD4+CD25+ T cells in different immunological systems. An isotype-matched control antibody was used as a negative control. A week after the second and the fourth dose of FVIII, plasma samples were taken and tested for anti-FVIII antibodies. We found differences in titers of anti-FVIII antibodies between mice treated with anti-CD25 antibodies and control mice in Balb/c mice but not in C57BL/6J mice. Hemophilic Balb/c mice that had been pre-treated with anti-CD25 antibodies developed higher titers of anti-FVIII antibodies than mice that had been pre-treated with an isotype-matched control antibody. Differences were seen as a statistical trend (p=0.091) after two doses of FVIII and reached statistical significance (p=0.024) after four doses of FVIII. No differences in antibody titers were observed in hemophilic C57BL/6J mice. Our results strongly indicate that the ability of naturally occurring regulatory T cells to modulate anti-FVIII antibody responses in hemophilic mice depends on the genetic background of these mice. Immunoregulatory factors such as cytokines or chemokines as well as differences in the number and functional activity of naturally occurring regulatory T cells that are found in secondary lymphoid organs are likely to determine the regulatory capacity of these cells. Based on our results we conclude that differences in number and functional activity of naturally occurring regulatory T cells should be considered in the search for risk factors associated with the development of FVIII inhibitors in patients.

scholarly journals Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities

Blood ◽  
2009 ◽  
Vol 113 (11) ◽  
pp. 2426-2433 ◽  
Author(s):  
Fouad Eddahri ◽  
Sébastien Denanglaire ◽  
Fabrice Bureau ◽  
Rosanne Spolski ◽  
Warren J. Leonard ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Interleukin 6 ◽  
Cell Activation ◽  
B Cell Activation ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Helper Cells

Abstract The conditions leading to the activation/differentiation of T-helper (Th) cells dedicated for B-cell antibody production are still poorly characterized. We now demonstrate that interleukin-6 (IL-6) promotes the differentiation of naive T lymphocytes into helper cells able to promote B-cell activation and antibody secretion. IL-6–driven acquisition of B-cell help capacity requires expression of the signal transducer and activator of transcription 3 (STAT3), but not STAT4 or STAT6 transcription factors, suggesting that the ability to provide help to B cells is not restricted to a well-defined Th1 or Th2 effector population. T cell–specific STAT3-deficient mice displayed reduced humoral responses in vivo that could not be related to an altered expansion of CXCR5-expressing helper T cells. IL-6 was shown to promote IL-21 secretion, a cytokine that was similarly found to promote the differentiation of naive T cells into potent B-cell helper cells. Collectively, these data indicate that the ability to provide B-cell help is regulated by IL-6/IL-21 through STAT3 activation, independently of Th1, Th2, Th17, or follicular helper T cell (TFH) differentiation.

scholarly journals Activated CLL B Cells Variably Modulate microRNA-155 Levels in Naïve CD4+ T Cells, and the Direction and Magnitude of microRNA-155 Change Correlates with Th17 Levels and Clinical Course

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4402-4402
Author(s):  
Byeongho Jung ◽  
Gerardo Ferrer ◽  
Pui Yan Chiu ◽  
Rukhsana Aslam ◽  
Florencia Palacios ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Cell Activation ◽  
B Cell Activation ◽  
Mutation Status ◽  
Naive T Cells ◽  
Naïve T Cells

Abstract T-helper 17 (Th17) cells constitute a subset of T cells that characteristically secrete IL-17. In addition to their normal adaptive immune functions, Th17 cells also play roles in supporting dysfunctional immune responses found in autoimmunity and cancer. Several studies suggest that Th17 cells play a protective role in chronic lymphocytic leukemia (CLL). For example, CLL patients exhibit varied levels of circulating Th17 cells, and elevated levels positively correlate with better clinical outcome regardless of IGHV-mutation status. To understand this relationship and elucidate the cellular and molecular mechanisms of Th17 generation in CLL, in particular the role of microRNAs known to affect Th17 development, we investigated cross-talk between naïve CD4+ T cells and CLL B cells. Moreover, since intraclonal leukemic B-cell subpopulations differing in time since cell birth/division can exhibit different functional effects on antigen presentation, we explored the effect of B-cell activation on this T - leukemic B-cell dialogue and how it affects the generation of Th17 cells. To determine potential candidates differentially expressed in CLL, we conducted genome-wide single-cell expression analysis comparing fluorescence activated cell sorting (FACS)-purified mature Th17 cells (CD3+/CD4+/CD45+/CD161+/CCR6+/ CCR4+/CXCR3-) from CLL patients and healthy donors. Selected candidate genes met the criteria of >7-fold increase in expression in CLL, adjusted p-value <1.5 x 10-6, and link to lymphocyte biology. Among selected candidates, microRNA-155 (miR-155), a critical regulator of Th17 differentiation, was found. Follow-up real time, quantitative PCR (RT-qPCR) analyses indicated a significant increase (P < 0.01) in miR-155 expression in CLL Th17 cells as compared to Th17 cells from healthy controls. Since there was no difference in expression between naïve T cells (CD3+/CD4+/CD62L+/CD45RO-) cells, this suggested a CLL-unique mechanism of miR-155 modulation. To determine whether CLL cells directly influence miR-155 levels in naïve CD4+ T cells, co-culture experiments using autologous leukemic or healthy B cells were carried out. FACS-purified peripheral blood naïve CD4+ T cells and B cells from CLL patients and from age-matched healthy controls were co-cultured for 3 days, and expression of T-cell miR-155 was determined by RT-qPCR. In the presence of unstimulated CLL or healthy B cells, miR-155 expression in naïve T cells remained unchanged across all co-cultures. However, upon activation, healthy and leukemic B cells exerted differential effects on miR-155 expression in autologous naïve T cells. In the presence of autologous healthy B cells pre-activated with CpG-ODN2006 and IL-15, miR-155 expression in healthy naïve T cells was significantly increased (P = 0.0313) across all samples. Conversely, CLL naïve T cells co-cultured with autologous, pre-activated leukemic B cells showed heterogeneous modulation of miR-155. Of interest, the magnitude and direction of miR-155 changes in the autologous CLL co-cultures positively correlated not only with circulating Th17 levels (P = 0.019), as determined by flow cytometry, but also with patient time to first treatment (P = 0.0003). Moreover, when samples were divided into 2 groups based on an increase or decrease in miR-155 levels after exposure to activated compared to resting CLL B cells, a significant difference was seen with median survival of 237 months and 67 months, respectively (P = 0.005). Consistent with previous observations from our lab, this correlation was independent of various prognostic markers, including IGHV-mutation status. Our results suggest the existence of a miR-155 modulatory mechanism mediated by CLL B cells that differs based on leukemic B-cell activation state and the degree of change occurring when naïve T cells are exposed to resting vs. activated B cells. Moreover, this variable effect in CLL patients differs from that in normal individuals, and the effect influences number of Th17 cells and patient outcome. Studies are underway to determine the effects that leukemic B cells, unstimulated or CpG-ODN2006 + IL-15 stimulated, have on autologous naïve T-cell maturation into Th17 cells, and the extent that this process depends on the variable miR-155 modulatory capacity of leukemic B cells. Disclosures Chiorazzi: Janssen, Inc: Consultancy; AR Pharma: Equity Ownership.

Friend retrovirus infection of myeloid dendritic cells impairs maturation, prolongs contact to naïve T cells, and favors expansion of regulatory T cells

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 3949-3958 ◽  
Author(s):  
Sandra Balkow ◽  
Frank Krux ◽  
Karin Loser ◽  
Jan U. Becker ◽  
Stephan Grabbe ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Immune Escape ◽  
Cell Contact ◽  
Myeloid Dendritic Cells ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Friend Retrovirus

Abstract Retroviruses have developed immunmodulatory mechanisms to avoid being attacked by the immune system. The mechanisms of this retrovirus-associated immune suppression are far from clarified. Dendritic cells (DCs) have been attributed a decisive role in these pathogenic processes. We have used the Friend retrovirus (FV) mouse model in order to acquire further knowledge about the role of infection of DCs in virus-induced immunosuppression. About 20% of the myeloid DCs that were generated from the bone marrow of FV-infected mice carried FV proteins. The infection was productive, and infected DCs transmitted the virus in cell culture and in vivo. FV infection of DCs led to a defect in DC maturation, as infected cells expressed very little costimulatory molecules. Live imaging analysis of the cell contact between DCs and T cells revealed prolonged contacts of T cells with infected DCs compared with uninfected DCs. Although naive T cells were still activated by FV-infected DCs, this activation did not result in antigen-specific T-cell proliferation. Interestingly, infected DCs expanded a population of Foxp3+ regulatory T cells with immunosuppressive potential, suggesting that the contact between naive T cells and retrovirus-infected DCs results in tolerance rather than immunity. Thus, retroviral infection of DCs leads to an expansion of regulatory T cells, which might serve as an immune escape mechanism of the virus.

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