scholarly journals Antigen presentation by resting B cells. Radiosensitivity of the antigen-presentation function and two distinct pathways of T cell activation.

1984 ◽  
Vol 159 (3) ◽  
pp. 881-905 ◽  
Author(s):  
J D Ashwell ◽  
A L DeFranco ◽  
W E Paul ◽  
R H Schwartz
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Antigen Presentation ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
B Cell Activation ◽  
Antigen Presenting

In this report we have examined the ability of small resting B cells to act as antigen-presenting cells (APC) to antigen-specific MHC-restricted T cells as assessed by either T cell proliferation or T cell-dependent B cell stimulation. We found that 10 of 14 in vitro antigen-specific MHC-restricted T cell clones and lines and three of four T cell hybridomas could be induced to either proliferate or secrete IL-2 in the presence of lightly irradiated (1,000 rads) purified B cells and the appropriate foreign antigen. All T cell lines and hybridomas were stimulated to proliferate or make IL-2 by macrophage- and dendritic cell-enriched populations and all T cells tested except one hybridoma caused B cell activation when stimulated with B cells as APC. Furthermore, lightly irradiated, highly purified syngeneic B cells were as potent a source of APC for inducing B cell activation as were low density dendritic and macrophage-enriched cells. Lymph node T cells freshly taken from antigen-primed animals were also found to proliferate when cultured with purified B cells and the appropriate antigen. Thus, small resting B cells can function as APC to a variety of T cells. This APC function was easily measured when the cells were irradiated with 1,000 rads, but was greatly diminished or absent when they were irradiated with 3,300 rads. Thus, the failure of some other laboratories to observe this phenomenon may be the result of the relative radiosensitivity of the antigen-presenting function of the B cells. In addition, this radiosensitivity allowed us to easily distinguish B cell antigen presentation from presentation by the dendritic cell and macrophage, as the latter was resistant to 3,300 rads. Finally, one T cell clone that failed to proliferate when B cells were used as APC was able to recruit allogeneic B cells to proliferate in the presence of syngeneic B cells and the appropriate antigen. This result suggests that there are at least two distinct pathways of activation in T cells, one that leads to T cell proliferation and one that leads to the secretion of B cell recruitment factor(s).

scholarly journals T Cell Accumulation in B Cell Follicles Is Regulated by Dendritic Cells and Is Independent of B Cell Activation

2003 ◽  
Vol 197 (2) ◽  
pp. 195-206 ◽  
Author(s):  
Simon Fillatreau ◽  
David Gray
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Cell Accumulation ◽  
Antigen Presenting ◽  
Deficient Mice

We investigated the mechanism of CD4 T cell accumulation in B cell follicles after immunization. Follicular T cell numbers were correlated with the number of B cells, indicating B cell control of the niche that T cells occupy. Despite this, we found no role for B cells in the follicular migration of T cells. Instead, T cells are induced to migrate into B cell follicles entirely as a result of interaction with dendritic cells (DCs). Migration relies on CD40-dependent maturation of DCs, as it did not occur in CD40-deficient mice but was reconstituted with CD40+ DCs. Restoration was not achieved by the activation of DCs with bacterial activators (e.g., lipopolysaccharide, CpG), but was by the injection of OX40L–huIgG1 fusion protein. Crucially, the up-regulation of OX40L (on antigen-presenting cells) and CXCR-5 (on T cells) are CD40-dependent events and we show that T cells do not migrate to follicles in immunized OX40-deficient mice.

scholarly journals Expression and functional significance of an additional ligand for CTLA-4

1993 ◽  
Vol 90 (23) ◽  
pp. 11054-11058 ◽  
Author(s):  
D J Lenschow ◽  
G H Su ◽  
L A Zuckerman ◽  
N Nabavi ◽  
C L Jellis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
T Cell Proliferation ◽  
Antigen Presenting

Effective T-cell activation requires antigen/major histocompatibility complex engagement by the T-cell receptor complex in concert with one or more costimulatory molecules. Recent studies have suggested that the B7 molecule, expressed on most antigen presenting cells, functions as a costimulatory molecule through its interaction with CD28 on T cells. Blocking the CD28/B7 interaction with CTLA4Ig inhibits T-cell activation in vitro and induces unresponsiveness. We demonstrate that another molecule(s), termed B7-2, is expressed constitutively on dendritic cells, is differentially regulated on B cells, and costimulates naive T cells responding to alloantigen. B7-2 is up-regulated by lipopolysaccharide in < 6 hr and is maximally expressed on the majority of B cells by 24 hr. In contrast, B7 is detected only on a subset of activated B cells late (48 hr) after stimulation. In addition, Con A directly induces B7-2 but not B7 expression on B cells. Finally, although both anti-B7 monoclonal antibodies and CTLA4Ig blocked T-cell proliferation to antigen-expressing B7 transfectants, only CTLA4Ig had any significant inhibitory effect on T-cell proliferation to antigens expressed on natural antigen presenting cells, such as dendritic cells. Thus, B7 is not the only costimulatory molecule capable of initiating T-cell responses since a second ligand, B7-2, can provide a necessary second signal for T-cell activation.

scholarly journals Induction of Peripheral T Cell Tolerance by Antigen-Presenting B Cells. II. Chronic Antigen Presentation Overrules Antigen-Presenting B Cell Activation

2006 ◽  
Vol 176 (7) ◽  
pp. 4021-4028 ◽  
Author(s):  
Giorgio Raimondi ◽  
Ivan Zanoni ◽  
Stefania Citterio ◽  
Paola Ricciardi-Castagnoli ◽  
Francesca Granucci
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Antigen Presentation ◽  
Cell Activation ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
B Cell Activation ◽  
Antigen Presenting

scholarly journals Abortive Proliferation of Rare T Cells Induced by Direct or Indirect Antigen Presentation by Rare B Cells In Vivo

1998 ◽  
Vol 187 (10) ◽  
pp. 1611-1621 ◽  
Author(s):  
Sarah E. Townsend ◽  
Christopher C. Goodnow
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Antigen Presentation ◽  
Cell Fate ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Presenting Cells ◽  
Antigen Presenting

Antigen-specific B cells are implicated as antigen-presenting cells in memory and tolerance responses because they capture antigens efficiently and localize to T cell zones after antigen capture. It has not been possible, however, to visualize the effect of specific B cells on specific CD4+ helper T cells under physiological conditions. We demonstrate here that rare T cells are activated in vivo by minute quantities of antigen captured by antigen-specific B cells. Antigen-activated B cells are helped under these conditions, whereas antigen-tolerant B cells are killed. The T cells proliferate and then disappear regardless of whether the B cells are activated or tolerant. We show genetically that T cell activation, proliferation, and disappearance can be mediated either by transfer of antigen from antigen-specific B cells to endogenous antigen-presenting cells or by direct B–T cell interactions. These results identify a novel antigen presentation route, and demonstrate that B cell presentation of antigen has profound effects on T cell fate that could not be predicted from in vitro studies.

Chronic Lymphocytic Leukemia Cells Acquire a Regulatory B-Cell Phenotype Modified By PD1 Signaling

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3319-3319 ◽  
Author(s):  
Shimrit Ringelstein-Harlev ◽  
Irit Avivi ◽  
Shoham Shivtiel-Arad ◽  
Tami Katz
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Immune Modulation ◽  
Lymphocytic Leukemia ◽  
T Cell Proliferation ◽  
Cell Contact

Abstract Introduction: Chronic lymphocytic leukemia (CLL) cells utilize several mechanisms of survival, some propagating proliferation and preventing apoptosis through intrinsic cell cycle signals, and others suppressing anti-tumor immune responses. Patients often present with a predominant population of regulatory T-cells (Tregs), and general features of T-cell exhaustion. Given the unique phenotype of CLL cells and the observed T-cell abnormalities we hypothesized that these cells function as regulatory B-cells (Bregs). Bregs, mostly explored in the autoimmune disease setting, produce interleukin-10 (IL10), which mediates attenuation of effector T-cell responses and enhances regulatory activity. These features have also been suggested to be responsible for weakening of anti-tumor immune responses. Breg activation requires stimulation of various combinations of Toll-like receptors (TLRs), the B-cell receptor (BCR) and CD40. Our previous studies have demonstrated that TLR9-stimulated CLL cells "acquire" Breg markers as well as PD1 and PDL1, which, while not being classic Breg discriminators, are established players in immune modulation. Moreover, such stimulation resulted in inhibition of proliferation of autologous T-cells. The current study aimed to further explore the regulatory characteristics of CLL cells focusing on additional suppressive mechanisms that may have a role in CLL immune evasion, particularly, the PD1/PDL1 axis. Methods: B-cells were isolated from peripheral blood mononuclear cells (PBMCs) of untreated CLL patients (Rai stages 0-IV). These B-CLL cells were stimulated with TLR-9 agonist (ODN) or CD40 ligand (CD40L) followed by their co-culture with isolated autologous CD4+ T cells. The regulatory features of B-CLL cells were studied by testing their effect on T cells. Their proliferation was evaluated using the CFSE method following stimulation with anti-CD3/CD28 antibodies and IL2; induction of Tregs (CD4+CD25highFoxp3+ population) was assessed by FACS analysis. The involvement of the PD1/PDL1 axis was examined by incubating B-cells with antiPD1 neutralizing antibodies prior to co-culture. Cell contact dependence was evaluated by plating B-cells in hanging cell culture inserts denying B and T cell contact while allowing flow of small soluble molecules. Results: CLL cells stimulated with ODN or CD40L, induced a significant increase in Tregs: 1.35±0.1-fold (p=0.03, N=12) for ODN and 1.7±0.2-fold (p=0.008, N=14) for CD40L, occurring in 68% and 80% of patients, respectively, while co-culture with unstimulated B-CLL cells did not result in the expansion of the Treg population. Treg induction was observed only under contact conditions (N=5), suggesting that this regulatory function requires cell-to-cell contact and cannot be carried out solely by secreted factors like IL10. Neutralization of PD1 on CLL B-cells affects both Treg induction and T-cell proliferation. Following CD40L stimulation, a 1.3-fold reduction in Treg percentage was observed when PD1 signaling was blunted (N=10). In contrast, PD1 blockage of ODN-stimulated CLL cells did not reduce Treg induction; however, it did adversely affect inhibition of T-cell proliferation (10%-decrease in inhibited T-cells; N=6). Conclusions: CLL cells "acquire" a Breg phenotype and function, inhibiting T-cell proliferation and inducing Tregs. These properties, while working together to promote immune regulation and cancer evasion, are elicited by different ligands in the cell environment and are likely to be mediated via separate pathways. The involvement of B-cell-associated PD1 in the induction of Tregs and inhibition of T-cell proliferation suggests a biologic role of PD1 signaling in CLL cells, strengthening the Breg phenotype. The current study has shown that CLL cells recruit several mechanisms operating cooperatively to support immune modulation and promote their survival. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effects of Friend Virus Infection and Regulatory T Cells on the Antigen Presentation Function of B Cells

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Tyler C. Moore ◽  
Ronald J. Messer ◽  
Lorena M. Gonzaga ◽  
Jennifer M. Mather ◽  
Aaron B. Carmody ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Cell Activation ◽  
T Cell Responses ◽  
B Cell Activation ◽  
Friend Virus ◽  
Cell Responses

ABSTRACTFriend virus (FV) is a naturally occurring mouse retrovirus that infects dividing cells of the hematopoietic lineage, including antigen-presenting cells (APCs). The infection of APCs by viruses often induces their dysfunction, and it has been shown that FV infection reduces the ability of dendritic cells (DCs) to prime critical CD8+T cell responses. Nonetheless, mice mount vigorous CD8+T cell responses, so we investigated whether B cells might serve as alternative APCs during FV infection. Directex vivoanalysis of B cells from FV-infected mice revealed that infected but not uninfected B cells upregulated expression of the costimulatory molecules CD80, CD86, and CD40, as well as major histocompatibility complex class II (MHC-II) molecules. Furthermore,in vitrostudies showed that, compared to uninfected B cells from the same mice, the FV-infected B cells had significantly enhanced APC function, as measured by their capacity to prime CD8+T cell activation and proliferation. Thus, in contrast to DCs, infection of B cells with FV enhanced their APC capacity and ability to stimulate the CD8+T cell responses essential for virus control. FV infections also induce the activation and expansion of regulatory T cells (Tregs), so it was of interest to determine the impact of Tregs on B cell activation. The upregulation of costimulatory molecule expression and APC function of B cells was even more strongly enhanced byin vivodepletion of regulatory T cells than infection. Thus, Tregs exert potent homeostatic suppression of B cell activation that is partially overcome by FV infection.IMPORTANCEThe primary role of B cells in immunity is considered the production of pathogen-specific antibodies, but another, less-well-studied, function of B cells is to present foreign antigens to T cells to stimulate their activation and proliferation. Dendritic cells (DCs) are considered the most important antigen-presenting cells (APCs) for CD8+T cells, but DCs lose APC function when infected with Friend virus (FV), a model retrovirus of mice. Interestingly, B cells were better able to stimulate CD8+T cell responses when they were infected with FV. We also found that the activation status of B cells under homeostatic conditions was potently modulated by regulatory T cells. This study illustrates an important link between B cell and T cell responses and illustrates an additional mechanism by which regulatory T cells suppress critical T cell responses during viral infections.

Chronic Lymphocytic Leukemia Cells Exhibit Inhibitory Properties of Regulatory B Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3874-3874
Author(s):  
Shimrit Ringelstein-Harlev ◽  
Irit Avivi ◽  
Lina Bisharat ◽  
Tamar Katz
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Fold Increase ◽  
Lymphocytic Leukemia ◽  
T Cell Proliferation ◽  
Cell Contact ◽  
Stimulation Of

Abstract Abstract 3874 Background: Chronic lymphocytic leukemia (CLL) is a mature B-cell malignancy, characterized by distinct immune suppression rendering both tumor cells and invading pathogens invisible to the immune system. However, CLL cells also display profound immune sensitivity as proven by long-term remissions achieved with allogeneic bone marrow transplantation. Many phenotypic properties of B-CLL cells resemble a subset of B-cells, studied mostly in autoimmunity and termed regulatory B cells (Bregs). Bregs are thought to suppress CD4+ T-cell mediated immune responses, directly through cell contact and indirectly through inhibitory cytokines. This study aims to define whether malignant B-CLL cells exhibit Breg suppressive properties, contributing to immune dysfunction in this disease. Methods: B-cells were isolated from peripheral blood mononuclear cells (PBMCs) of untreated CLL patients (Rai stages 0-IV) using immunomagnetic separation (STEMCELL technologies). Naïve cells and those stimulated with B-cell activators TLR-9 agonist or CD40Ligand (CD40L) were analyzed by FACS for Breg phenotypic markers and intracellular IL-10. Additionally, B-CLL cell effects on autologous CD4+ T cells (isolated by immunomagnetic beads; Miltenyi Biotec) were studied. T-cells were stimulated with anti-CD3/CD28 antibodies and IL-2, and exposed to B-cells either directly or through hanging cell culture inserts (Millipore) preventing physical cell-cell contact. T-cell proliferation was assessed using the carboxyfluorescein diacetate succinimidyl ester (CFSE) method and phenotype was analyzed by FACS. Results: B-cell phenotype was studied in 11 patients. Breg markers (CD5, CD38, CD25 and intracellular IL-10) as well as inhibitory molecules PD-1 and PDL-1 were expressed at high levels on B-CLL cells (62%, 37%, 50%, 52%, 29%, 61%, respectively), although not every patient expressed all markers. These expression levels were higher than those reported for normal peripheral blood B-cells. TLR-9 stimulation of B-CLL cells resulted in a 5.7-fold increase in expression of CD25 in 77% of patients. Increments were also observed in IL-10 (1.9-fold; 62% of patients), PDL-1 (1.96-fold; 83% of patients) and PD-1 (2.19-fold; 57% of patients). Of 13 patients whose T-cell proliferation potential was evaluated after exposure to B-CLL cells, proliferation was induced in only 69%; in the other 31% (4 patients) no proliferation was observed; moreover, inhibition was demonstrated in one of them. Among the former group only 33% of patients expressed CD25 on their B-cells, whereas within the latter group, 75% of patients' B-cells were CD25-positive. Stimulation of B-CLL cells with TLR-9 markedly increased their inhibitory capacity (72% of 11 patients tested), while CD40L stimulation caused a weaker effect (50% of 6 patients tested). T-cell proliferation remained unchanged when evaluated using a Transwell system versus a contact system, as demonstrated in 3 of 4 experiments. T-cells exposed to B-CLL cells altered the ratio of CD25high vs. CD25low T-cells in favor of CD25 high cells (2.44-fold increase for stimulation with naïve B-CLL cells, 4.94-fold increase with TLR-9 stimulated cells; in all the 5 tested patients). Conclusions: Previously identified Breg markers as well as PD-1 and PDL-1 were highly expressed in B-CLL cells, supporting the role of these cells in shaping an immune tolerant environment, enabling tumor growth. Stimulation of B-CLL cells with TLR-9 agonist enhanced this phenotype and resulted in consistent inhibition of T-cell proliferation, likely to be independent of cell-to-cell contact. These findings demonstrate the presence of Breg features within the CLL clone. The observed alterations in CD4+CD25+ T-cell populations after exposure to B-CLL cells suggest induction of T-regulatory cells, another mechanism supposedly used by Bregs for immune suppression. The enhancement of Breg properties in B-CLL cells following B-cell activation can serve as a platform for further studies of the innate regulatory mechanisms utilized by tumor cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Activation and Tolerance in CD4+ T Cells Reactive to an Immunoglobulin Variable Region

2004 ◽  
Vol 200 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Christopher M. Snyder ◽  
Katja Aviszus ◽  
Ryan A. Heiser ◽  
Daniel R. Tonkin ◽  
Amanda M. Guth ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Variable Region ◽  
Cell Receptor ◽  
B Cell Activation ◽  
Antibody Diversity ◽  
Helper Activity

Antibody diversity creates an immunoregulatory challenge for T cells that must cooperate with B cells, yet discriminate between self and nonself. To examine the consequences of T cell reactions to the B cell receptor (BCR), we generated a transgenic (Tg) line of mice expressing a T cell receptor (TCR) specific for a κ variable region peptide in monoclonal antibody (mAb) 36-71. The κ epitope was originally generated by a pair of somatic mutations that arose naturally during an immune response. By crossing this TCR Tg mouse with mice expressing the κ chain of mAb 36-71, we found that κ-specific T cells were centrally deleted in thymi of progeny that inherited the κTg. Maternally derived κTg antibody also induced central deletion. In marked contrast, adoptive transfer of TCR Tg T cells into κTg recipients resulted in T and B cell activation, lymphadenopathy, splenomegaly, and the production of IgG antichromatin antibodies by day 14. In most recipients, autoantibody levels increased with time, Tg T cells persisted for months, and a state of lupus nephritis developed. Despite this, Tg T cells appeared to be tolerant as assessed by severely diminished proliferative responses to the Vκ peptide. These results reveal the importance of attaining central and peripheral T cell tolerance to BCR V regions. They suggest that nondeletional forms of T tolerance in BCR-reactive T cells may be insufficient to preclude helper activity for chromatin-reactive B cells.

scholarly journals Interleukin 4 production by CD4+ T cells from allergic individuals is modulated by antigen concentration and antigen-presenting cell type.

1995 ◽  
Vol 181 (3) ◽  
pp. 1081-1089 ◽  
Author(s):  
H Secrist ◽  
R H DeKruyff ◽  
D T Umetsu
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Interleukin 4 ◽  
T Cell Proliferation ◽  
High Concentrations ◽  
Antigen Presenting

We have previously shown that CD4+ T cells from allergic individuals are predisposed to produce interleukin (IL)-4 in response to allergens, and that allergen immunotherapy greatly reduced IL-4 production in an allergen-specific fashion. The mechanism that results in the reduction of IL-4 synthesis in treated individuals is unknown, but because clinical improvement during immunotherapy is associated with the administration of the highest doses of allergen, we hypothesized that high concentration of allergen results in the downregulation of IL-4 synthesis in CD4+ T cells. In this report, we demonstrated that CD4+ T cells from allergic donors produced high levels of IL-4 when stimulated with low concentrations of allergen (0.003-0.01 micrograms/ml), particularly when B cell-enriched populations presented the antigen. In contrast, the same responding CD4+ T cell population produced little IL-4 when stimulated with high concentrations of allergen (10-30 micrograms/ml), especially when monocytes were used as antigen-presenting cells (APC). The quantity of IL-4 produced was also found to be inversely related to the extent of proliferation of the CD4+ T cells in response to allergen/antigen; maximal proliferation of CD4+ T cells occurred in response to high concentrations of antigen when IL-4 production was minimal. Antigen presentation by B cell-enriched populations, instead of monocytes, induced less CD4+ T cell proliferation, but induced much greater IL-4 synthesis. Moreover, the addition of increasing numbers of APC (either B cells or monocytes) to cultures containing a constant number of responder T cells resulted in increased T cell proliferation and decreased IL-4 production. These results indicate that the circumstances under which memory T cells are activated, as well as the strength of the proliferative signal to T cells, greatly affect the quantity of IL-4 produced. Thus, our observations that the cytokine profile of allergen-specific memory CD4+ T cells can indeed be modulated by the antigen dose and APC type suggest that methods that preferentially enhance allergen uptake by monocytes and that enhance T cell proliferation will improve the clinical efficacy of immunotherapy in the treatment of allergic disease.

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