scholarly journals Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Carolina Prado ◽  
Francisco Osorio-Barrios ◽  
Paulina Falcón ◽  
Alexandra Espinoza ◽  
Juan José Saez ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
B Cells ◽  
Animal Models ◽  
B Cell ◽  
Cns Autoimmunity ◽  
Eae Model ◽  
Anti Inflammatory

Abstract Background Recent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of immune cells plays an important role in the physiopathology of inflammatory disorders. Multiple sclerosis (MS) is an inflammatory disease involving a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Evidence from animal models has suggested that B cells play a fundamental role as antigen-presenting cells (APC) re-stimulating CD4+ T cells in the CNS as well as regulating T-cell response by mean of inflammatory or anti-inflammatory cytokines. Here, we addressed the role of the dopamine receptor D3 (DRD3), which displays the highest affinity for dopamine, in B cells in animal models of MS. Methods Mice harbouring Drd3-deficient or Drd3-sufficient B cells were generated by bone marrow transplantation into recipient mice devoid of B cells. In these mice, we compared the development of experimental autoimmune encephalomyelitis (EAE) induced by immunization with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide (pMOG), a model that leads to CNS-autoimmunity irrespective of the APC-function of B cells, or by immunization with full-length human MOG protein (huMOG), a model in which antigen-specific activated B cells display a fundamental APC-function in the CNS. APC-function was assessed in vitro by pulsing B cells with huMOG-coated beads and then co-culturing with MOG-specific T cells. Results Our data show that the selective Drd3 deficiency in B cells abolishes the disease development in the huMOG-induced EAE model. Mechanistic analysis indicates that although DRD3-signalling did not affect the APC-function of B cells, DRD3 favours the CNS-tropism in a subset of pro-inflammatory B cells in the huMOG-induced EAE model, an effect that was associated with higher CXCR3 expression. Conversely, the results show that the selective Drd3 deficiency in B cells exacerbates the disease severity in the pMOG-induced EAE model. Further analysis shows that DRD3-stimulation increased the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in the pMOG-induced EAE model. Conclusions Our findings demonstrate that DRD3 in B cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B cells with APC-function and promoting CNS-homing of B cells with anti-inflammatory features. Thus, these results show DRD3-signalling in B cells as a critical regulator of CNS-autoimmunity.

scholarly journals Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

2020 ◽  
Author(s):  
Carolina Prado ◽  
Francisco Osorio-Barrios ◽  
Alexandra Espinoza ◽  
Juan J Saez ◽  
María I Yuseff ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
T Cell ◽  
B Cells ◽  
Animal Models ◽  
B Cell ◽  
T Cell Response ◽  
Autoimmune Response ◽  
Cns Autoimmunity ◽  
Anti Inflammatory

Abstract Background: Recent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of adaptive and innate immune cells plays an important role in the physiopathology of inflammatory disorders. Multiple sclerosis (MS) is an inflammatory disease involving a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Evidence from animal models has suggested that B-cells play a fundamental role as antigen-presenting cells (APC) re-stimulating CD4+ T-cells in the CNS as well as regulating T-cell response by mean of inflammatory or anti-inflammatory cytokines. Here we addressed the role of the dopamine receptor D3 (DRD3), which display the highest affinity for dopamine, in B-cells in animal models of MS.Methods: Mice harbouring Drd3-deficient or Drd3-suficient B-cells were generated by bone marrow transplantation into recipient mice devoid of B-cells. In these mice we compare the development of experimental autoimmune encephalomyelitis (EAE) induced by immunization with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide (pMOG), a model that leads to CNS-autoimmunity irrespective of the APC function of B-cells, or by immunization with full-length human MOG protein (huMOG), a model in which antigen-specific activated B-cells display a fundamental APCs function in the CNS. Results: Our data shows that, by promoting the expression of the chemokine receptor CXCR3 in autoreactive B-cells, DRD3-stimulation favours the CNS-tropism in a subset of B-cells that act as APC in the CNS, which is fundamental for disease development. Furthermore, we found that DRD3- stimulation induced the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in a CNS-autoimmunity model independent of the APC function of B-cells.Conclusion: Our findings demonstrate that DRD3-stimulation in B-cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B-cells with APC function, and also promoting CNS-homing of B-cells with anti-inflammatory features. Thus, these results show DRD3-stimulation in B-cells as a key regulator of CNS-autoimmunity.

scholarly journals Dopaminergic Stimulation Leads B-cell Infiltration into the Central Nervous System upon Autoimmunity

2021 ◽  
Author(s):  
Carolina Prado ◽  
Francisco Osorio-Barrios ◽  
Alexandra Espinoza ◽  
Juan J Saez ◽  
María I Yuseff ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
T Cell ◽  
B Cells ◽  
Animal Models ◽  
B Cell ◽  
T Cell Response ◽  
Autoimmune Response ◽  
Cns Autoimmunity ◽  
Anti Inflammatory

Abstract Background. Recent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of adaptive and innate immune cells plays an important role in the physiopathology of inflammatory disorders. Multiple sclerosis (MS) is an inflammatory disease involving a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Evidence from animal models has suggested that B-cells play a fundamental role as antigen-presenting cells (APC) re-stimulating CD4+ T-cells in the CNS as well as regulating T-cell response by mean of inflammatory or anti-inflammatory cytokines. Here we addressed the role of the dopamine receptor D3 (DRD3), which display the highest affinity for dopamine, in B-cells in animal models of MS. Methods. Mice harbouring Drd3-deficient or Drd3-suficient B-cells were generated by bone marrow transplantation into recipient mice devoid of B-cells. In these mice we compare the development of experimental autoimmune encephalomyelitis (EAE) induced by immunization with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide (pMOG), a model that leads to CNS-autoimmunity irrespective of the APC function of B-cells, or by immunization with full-length human MOG protein (huMOG), a model in which antigen-specific activated B-cells display a fundamental APCs function in the CNS.Results. Our data shows that, by promoting the expression of the chemokine receptor CXCR3 in autoreactive B-cells, DRD3-stimulation favours the CNS-tropism in a subset of B-cells that act as APC in the CNS, which is fundamental for disease development. Furthermore, we found that DRD3- stimulation induced the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in a CNS-autoimmunity model independent of the APC function of B-cells.Conclusions. Our findings demonstrate that DRD3-stimulation in B-cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B-cells with APC function, and also promoting CNS-homing of B-cells with anti-inflammatory features. Thus, these results show DRD3-signalling in B-cells as a key regulator of CNS-autoimmunity.

scholarly journals Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

2021 ◽  
Author(s):  
Carolina Prado ◽  
Francisco Osorio-Barrios ◽  
Alexandra Espinoza ◽  
Juan J Saez ◽  
María I Yuseff ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Response ◽  
Autoimmune Response ◽  
Cns Autoimmunity ◽  
Anti Inflammatory

Abstract Multiple sclerosis (MS) involves a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Previous evidence has suggested that B-cells play a fundamental role as antigen-presenting cells (APC) in mouse models of MS re-stimulating CD4+ T-cells in the CNS as well as regulating the T-cell response by mean of inflammatory or anti-inflammatory cytokines. Despite an important dopaminergic regulation of T-cells has been previously described in MS, the effects of dopaminergic signalling in B-cells in this pathology remains unexplored. Here we addressed the role of the dopamine receptor D3 (DRD3), which display the highest affinity for dopamine, in B-cells in animal models of MS. Experimental autoimmune encephalomyelitis (EAE) was induced in mice harbouring Drd3-deficient or Drd3-suficient B-cells. Our data shows that, by promoting the expression of the chemokine receptor CXCR3 in autoreactive B-cells, DRD3-stimulation favours the CNS-tropism in a subset of B-cells that act as APC in the CNS, which is fundamental for disease development. Furthermore, we found that DRD3-stimulation induced the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in a CNS-autoimmunity model independent of the APC function of B-cells. Our findings demonstrate that DRD3-stimulation in B-cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B-cells with APC function, and also promoting CNS-homing of B-cells with anti-inflammatory features. Thus, these results show DRD3-stimulation in B-cells as a key regulator of CNS-autoimmunity.

scholarly journals New Therapeutic Approach for Central Nervous System Lymphoma By Intracerebroventricular Delivery of CD19CAR T Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2161-2161
Author(s):  
Xiuli Wang ◽  
Ryan Urak ◽  
Walter Miriam ◽  
Laura Lim ◽  
Brenda Aguilar ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
B Cell ◽  
Central Nervous System Lymphoma ◽  
Car T Cell ◽  
Car T ◽  
Systemic Lymphoma ◽  
Cns Lymphomas

Abstract Central nervous system lymphoma (CNSL) is a lymphoid malignancy in which tumors from lymph tissue start in the brain, spinal cord, eye, and/or meninges (primary CNSL) or present as a result of metastasis from initial systemic sites to the CNS (secondary CNSL). The most common CNS lymphomas (about 90%) are B-cell lymphomas. The incidence of primary CNS lymphoma has been increasing over the past 20 years. Multifocal lesions are common. CNS lymphomas carry a worse prognosis than systemic lymphoma. Only a few chemotherapeutic drugs can cross and achieve a therapeutic concentration in the CNS. Therefore, effective treatment is limited and the outcome of disease in relapsed or refractory setting is poor. Recent studies show that intraventricular delivery of rituximab in CNS lymphomas is well tolerated. T cell products that are genetically engineered with chimeric antigen receptors (CARs) targeting CD19 have broad application for adoptive therapy of B cell lineage malignancies and have shown tremendous potential in treatment of systemic lymphoma. In all CD19CAR T cell trials, T cell products are administrated intravenously. CD19CAR T cell trafficking in cerebrospinal fluid (CSF) is frequently reported but most if not all protocols exclude patients with active CNS involvement. In this study, we set out to investigate the feasibility and efficacy of the use of CD19CAR T cells to treat CNSL. Methods and Results: Isolated naïve and central memory T cells (Tn/Tmem) were genetically modified with CD19CAR lentivirus and expanded in vitro for 14 days. 0.1x10^6 human B cell lymphoma Daudi cells were injected intracranially into NSG mice. Tumor was allowed to engraft for 5 days. We administered CD19CAR T cells via three different delivery routes: intracranial local infusion with 1x10^6 CD19CAR T cells (i.c), intracerebroventricular (i.c.v) administration with 1x10^6 cells to bypass the blood-brain barrier and target tumor throughout the entire CNS, and intravenous injection (i.v) with 3x10^6 cells. We repeatedly observed in 2 separate experiments (N=5 mice in each experiment) that both a single i.c infusion and a single i.c.v delivery of CD19CAR T cells were able to completely eradicated CNS lymphoma in all mice by day 14 post CAR T cell infusion; and that a single dose of i.v infusion induced significant anti-CNSL activity with a slightly delayed response as compared to i.c and i.c.v treatment and all mice achieved complete remission 21 days post T cell infusion. CAR T cells were detected in peripheral blood obtained from retro-orbital bleeding, not only in the i.v treated mice, but also in i.c.v treated mice 28 days after CAR T cell infusion, suggesting that i.c.v not only controls CNSL but may also play a role in immune surveillance for systemic tumors. To confirm this, we established an NSG CNS B cell lymphoma model by also inoculating subcutaneous tumors on the animal's flank, 3 weeks prior to i.c tumor injection into the same mouse. CD19CAR T cells were delivered via i.c.v 5 days after i.c. tumor injection. CAR T cell injection resulted in complete remission of both the brain tumor and the flank tumor 14 days after CAR T cell administration. In conclusion,intracerebroventricular delivery of CD19CAR T cells is a promising and feasible therapeutic approach for both primary central nervous system lymphoma and systemic lymphoma with concurrent CNS involvement. Disclosures No relevant conflicts of interest to declare.

scholarly journals Pathogenic T cell cytokines in multiple sclerosis

2019 ◽  
Vol 217 (1) ◽  
Author(s):  
Catriona A. Wagner ◽  
Pamela J. Roqué ◽  
Joan M. Goverman
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Young Adults ◽  
T Cell ◽  
Animal Models ◽  
Demyelinating Disease ◽  
The Central Nervous System ◽  
Autoimmune Etiology

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system that is believed to have an autoimmune etiology. As MS is the most common nontraumatic disease that causes disability in young adults, extensive research has been devoted to identifying therapeutic targets. In this review, we discuss the current understanding derived from studies of patients with MS and animal models of how specific cytokines produced by autoreactive CD4 T cells contribute to the pathogenesis of MS. Defining the roles of these cytokines will lead to a better understanding of the potential of cytokine-based therapies for patients with MS.

scholarly journals Expression of Tim-1 and Its Pathogenetic Role in Primary CNS Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2961-2961
Author(s):  
Momoko Nishikori ◽  
Wataru Kishimoto ◽  
Hiroshi Arima ◽  
Kotaro Shirakawa ◽  
Toshio Kitawaki ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Regulatory B Cells ◽  
A Cell

Abstract Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin’s lymphoma that arises within the central nervous system (CNS) as a primary lesion, most of which demonstrate diffuse large B-cell lymphoma (DLBCL) histology. However, CNS is recognized as an “immune sanctuary”, and it is not clear in what mechanism B cells develop tumor at this immunoprivileged site. In the past mouse models of multiple sclerosis and cerebral infarction, regulatory B cells, a population of B cells with high IL-10 producing capacity, were reported to have a function to migrate to CNS and suppress inflammation. As the IL-10 level is typically increased in the cerebrospinal fluid (CSF) of PCNSL patients, we hypothesized that PCNSL might originate from B cells that have a physiological role to produce IL-10 for suppressing unfavorable inflammation in CNS, such as regulatory B cells in mice. Recently, a cell surface molecule T cell immunoglobulin domain and mucin domain protein 1 (Tim-1) has been reported to be specifically expressed in the majority of regulatory B cells in mice. Tim-1 was originally identified as a costimulatory molecule on T cells that negatively regulates cellular immune response. Regulatory B cells in mice with defective Tim-1 mutation were reported to demonstrate a profound defect in IL-10 production, suggesting that Tim-1 plays an essential role in their IL-10 production. However, there has been no previous report on Tim-1 expression on human B-cells or B-cell lymphomas, or what function they may serve if it is present. We performed immunohistochemical staining of Tim-1 in various formalin-fixed paraffin embedded lymphoma samples. We observed strong expression of Tim-1 in PCNSL samples, in contrast to its lower expression in other DLBCL and follicular lymphoma samples. Expression of Tim-1 is also detected in a cell line derived from PCNSL (TK), as well as in several other B-cell lymphoma cell lines, by RT-PCR and western blot. As we detected spontaneous shedding of the ectodomain of Tim-1 in the culture media of Tim-1-expressing B-cell lymphoma cell lines, we examined whether Tim-1 can also be detected in the CSF of PCNSL patients. By ELISA, we detected soluble Tim-1 in the CSF of PCNSL patients with active disease, and found it undetectable after the successful treatment with chemo/radiotherapy. The level of soluble Tim-1 in the CSF was positively correlated with IL-10, and it is suggested that these two molecules are functionally related also in humans. In a patient with continuous Tim-1 detection in the CSF after chemotherapy while radiological examination could no longer detected any abnormality, subsequently manifested relapse in the brain. According to these findings, soluble Tim-1 in CSF may be expected to serve as a sensitive biomarker for PCNSL. To clarify the biological role of soluble Tim-1 in tumor microenvironment, we examined its effect on T cell function. We stimulated CD4+ and CD8+ T cells with or without soluble Tim-1 in vitro and compared their cytokine production. The result showed that, in the presence of soluble Tim-1, both IL-2 and IFN-g production was suppressed in CD8+ T cells. In conclusion, Tim-1 is expressed in PCNSL and shedding of extracellular domain of Tim-1, in addition to IL-10, may contribute to the immunosuppressive microenvironment of PCNSL. Disclosures No relevant conflicts of interest to declare.

scholarly journals B cell depletion impairs vaccination-induced CD8+ T cell responses in a type I interferon-dependent manner

2021 ◽  
pp. annrheumdis-2021-220435
Author(s):  
Theresa Graalmann ◽  
Katharina Borst ◽  
Himanshu Manchanda ◽  
Lea Vaas ◽  
Matthias Bruhn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
De Novo ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
T Cell Expansion

ObjectivesThe monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses.MethodsCD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens.ResultsRituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I.ConclusionsDepending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.

scholarly journals T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presenting as a Primary Central Nervous System Lymphoma

Rare Tumors ◽  
2015 ◽  
Vol 7 (4) ◽  
pp. 160-162 ◽  
Author(s):  
Pooja Advani ◽  
Jason Starr ◽  
Abhisek Swaika ◽  
Liuyan Jiang ◽  
Yushi Qiu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Electrical Properties and Anion Permeability of Doubly Rectifying Junctions in the Leech Central Nervous System

1988 ◽  
Vol 137 (1) ◽  
pp. 1-11
Author(s):  
Susan E. Acklin
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Action Potentials ◽  
Sodium Pump ◽  
Current Flow ◽  
Cell Movement ◽  
Voltage Dependent ◽  
Electrical Connections

A study has been made of the electrical connections between touch sensory (T) neurones in the leech central nervous system (CNS) which display remarkable double rectification: depolarization spreads in both directions although hyperpolarization spreads poorly. Tests were made to determine whether this double rectification was a property of the junctions themselves or whether it resulted from changes in the length constants of processes intervening between the cell body and the junctions. Following trains of action potentials, T cells and their fine processes within the neuropile became hyperpolarized through the activity of an electrogenie sodium pump. When any T cell was hyperpolarized by 25 mV by repetitive stimulation, hyperpolarization failed to spread to the T cells to which it was electrically coupled. Further evidence for double rectification of junctions linking T cells was provided by experiments in which Cl− was injected electrophoretically. Cl− injection into one T cell caused inhibitory potentials recorded in it to become reversed. After a delay, Cl− spread to reverse IPSPs in the coupled T cell. Movement of Cl−, like current flow, was dependent on membrane potential. When the T cell into which Cl− was injected was kept hyperpolarized, Cl− failed to move into the adjacent T cell. Upon release of the hyperpolarization in the injected T cell, Cl− moved and reversed IPSPs in the coupled T cell. Together these results indicate that the gating properties of channels linking T cells are voltage-dependent, such that depolarization of either cell allows channels to open whereas hyperpolarization causes them to close.

scholarly journals The role of H-2-linked genes in helper T cell function. VII. Expression of I region and immune response genes by B cells in bystander help assays.

1980 ◽  
Vol 152 (5) ◽  
pp. 1274-1288 ◽  
Author(s):  
P Marrack ◽  
J W Kappler
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
High Responder ◽  
Helper T Cells ◽  
Spleen Cells ◽  
Region Gene ◽  
Immunoglobulin Receptor

The mode of action by bystander helper T cells was investigated by priming (responder X nonresponder) (B6A)F1 T cells with poly-L-(Tyr, Glu)-poly-D,L-Ala--poly-L-Lys [(TG)-A--L] and titrating the ability of these cells to stimulate an anti-sheep red blood cell (SRBC) response of parental B cells and macrophages in the presence of (TG)-A--L. Under limiting T cell conditions, and in the presence of (TG)-A--L, (TG)-A--L-responsive T cells were able to drive anti-SRBC responses of high-responder C57BL/10.SgSn (B10) B cells and macrophages (M0), but not of low-responder (B10.A) B cells and M0. Surprisingly, the (TG)-A--L-driven anti-SRBC response of B10.A B cells was not restored by addition of high-responder acessory cells, in the form of (B6A)F1 peritoneal or irradiated T cell-depleted spleen cells, or in the form of B10 nonirradiated T cell-depleted spleen cells. These results suggested that (TG)-A--L-specific Ir genes expressed by B cells controlled the ability of these cells to be induced to respond to SRBC by (TG)-A--L-responding T cells, implying that direct contact between the SRBC-binding B cell precursor and the (TG)-A--L-responsive helper T cells was required. Analogous results were obtained for keyhold limpet hemocyanin (KLH)-driven bystander help using KLH-primed F1 T cells restricted to interact with cells on only one of the parental haplotypes by maturing them in parental bone marrow chimeras. It was hypothesized that bystander help was mediated by nonspecific uptake of antigen [(TG)-A--L or KLH] by SRBC-specific b cells and subsequent display of the antigen on the B cell surface in association with Ir of I-region gene products, in a fashion similar to the M0, where it was then recognized by helper T cells. Such an explanation was supported by the observation that high concentrations of antigen were required to elicit bystander help. This hypothesis raises the possibility of B cell processing of antigen bound to its immunoglobulin receptor and subsequent presentation of antigen to helper T cells.

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