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 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 ◽  
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.

Cultured Human B Cell APCs Expanded Using Il-4 and CD40 Ligand Preferentially Promote a Type 2 T Cell Response to Alloimmune Stimulation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2668-2668
Author(s):  
Abdul Tawab ◽  
Yoshiyuki Takahashi ◽  
Childs Richard ◽  
Kurlander J. Roger
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Response ◽  
Cd40 Ligand ◽  
T Cell Response ◽  
Ifn Γ

Abstract In vitro stimulation of human peripheral blood B cells with recombinant IL-4 and CD40 ligand (CD40L) markedly increases their expression of MHC and costimulatory molecules, thus enhancing antigenic peptide presentation to T cells. Because these cells proliferate extensively in vitro (unlike monocytes or dendritic cells), they represent a promising and convenient reagent for the generation and maintenance of antigen-specific T cells for use in a variety of experimental or therapeutic settings. However, the impact of this type of B cell APC on cytokine production by responder T cells has hitherto not been examined. To address this issue, we stimulated normal human T cells with either allogeneic B cells (generated in vitro) or with MNCs obtained from the same donor. After 7 days, T cells were washed and re-challenged with the same APCs. The resulting alloreactive cytokine response was measured using quantitative ELISPOT methods and expressed as the frequencies of IFN-γ, IL-4, and IL-5 producing cells per thousand responder cells added. B cell- and MNC-primed cell lines both produced vigorous lymphokine responses, but B cell-stimulated T cells consistently produced more IL-5 spots (mean of 265 vs. 98/1000 responders, p<0.002) and fewer IFN-γ spots (163 vs 386/1000 cells, p<0.005) than MNC-stimulated cells. Further, the ratio of IFN-γ to IL-5 spots was almost ten-fold lower in B cell-stimulated cultures compared to MNC-induced cultures (0.67 vs. 5.2, p<0.001). ELISPOT studies assessing the ratio of IFN-γ to IL-4 spots and ELISA assays comparing IFN-γ and IL-5 levels from culture supernatants demonstrated the same pattern of marked type 2 skewing by B cells. This pattern was unaffected by the presence of anti-IL-4 antibody suggesting type 2 skewing was not mediated by IL-4. Cytokine skewing produced by B cells or MNC could be partially reversed by swapping MNC and B cells during re-stimulation on day 7, but this plasticity was markedly reduced after 3 (weekly) cycles of B cell or MNC re-stimulation in vitro. Type 2 skewing by B cells was enhanced when monocytes were removed from responder T cell populations by either depleting CD14+ positive cells or by positive selection of T cells prior to stimulation. In contrast, type 2 polarization could be prevented using recombinant IL-12. Not all cells of B-cell origin share the same propensity to type 2 skewing observed with IL-4/CD40L-stimulated B cells; under identical conditions, EBV-transformed B cells stimulated alloimmune T cells to produce a strong type 1 cytokine response comparable to that produced by MNCs. In summary, IL-4/CD40L-stimulated B cells strongly promote a type 2 T cell response during primary alloimmune challenge; this skewing can become fixed after repeated B cell stimulation. Investigators using these cells as APC should be aware of this potential phenomenon, particularly during primary T cell responses. It is also important to consider the factors described above that may exacerbate or ameliorate this effect.

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 Priming of CD8+ T Cells during Central Nervous System Infection with a Murine Coronavirus Is Strain Dependent

2008 ◽  
Vol 82 (13) ◽  
pp. 6150-6160 ◽  
Author(s):  
Katherine C. MacNamara ◽  
Susan J. Bender ◽  
Ming Ming Chua ◽  
Richard Watson ◽  
Susan R. Weiss
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cns Infection ◽  
Cervical Lymph Nodes ◽  
T Cell Priming ◽  
The Brain

ABSTRACT Virus-specific CD8+ T cells are critical for protection against neurotropic coronaviruses; however, central nervous system (CNS) infection with the recombinant JHM (RJHM) strain of mouse hepatitis virus (MHV) elicits a weak CD8+ T-cell response in the brain and causes lethal encephalomyelitis. An adoptive transfer model was used to elucidate the kinetics of CD8+ T-cell priming during CNS infection with RJHM as well as with two MHV strains that induce a robust CD8+ T-cell response (RA59 and SJHM/RA59, a recombinant A59 virus expressing the JHM spike). While RA59 and SJHM/RA59 infections resulted in CD8+ T-cell priming within the first 2 days postinfection, RJHM infection did not lead to proliferation of naïve CD8+ T cells. While all three viruses replicated efficiently in the brain, only RA59 and SJHM/RA59 replicated to appreciable levels in the cervical lymph nodes (CLN), the site of T-cell priming during acute CNS infection. RJHM was unable to suppress the CD8+ T-cell response elicited by RA59 in mice simultaneously infected with both strains, suggesting that RJHM does not cause generalized immunosuppression. RJHM was also unable to elicit a secondary CD8+ T-cell response in the brain following peripheral immunization against a viral epitope. Notably, the weak CD8+ T-cell response elicited by RJHM was unique to CNS infection, since peripheral inoculation induced a robust CD8+ T-cell response in the spleen. These findings suggest that the failure of RJHM to prime a robust CD8+ T-cell response during CNS infection is likely due to its failure to replicate in the CLN.

scholarly journals Obligatory Requirement for Antibody in Recovery from a Primary Poxvirus Infection

2006 ◽  
Vol 80 (13) ◽  
pp. 6339-6344 ◽  
Author(s):  
Geeta Chaudhri ◽  
Vijay Panchanathan ◽  
Horst Bluethmann ◽  
Gunasegaran Karupiah
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Ectromelia Virus ◽  
B Cell Function

ABSTRACT To understand the correlates of protective immunity against primary variola virus infection in humans, we have used the well-characterized mousepox model. This is an excellent surrogate small-animal model for smallpox in which the disease is caused by infection with the closely related orthopoxvirus, ectromelia virus. Similarities between the two infections include virus replication and transmission, aspects of pathology, and development of pock lesions. Previous studies using ectromelia virus have established critical roles for cytokines and effector functions of CD8 T cells in the control of acute stages of poxvirus infection. Here, we have used mice deficient in B cells to demonstrate that B-cell function is also obligatory for complete virus clearance and recovery of the host. In the absence of B cells, virus persists and the host succumbs to infection, despite the generation of CD8 T-cell responses. Intriguingly, transfer of naive B cells or ectromelia virus-immune serum to B-cell-deficient mice with established infection allowed these animals to clear virus and fully recover. In contrast, transfer of ectromelia virus-immune CD8 T cells was ineffective. Our data show that mice deficient in CD8 T-cell function die early in infection, whereas those deficient in B cells or antibody production die much later, indicating that B-cell function becomes critical after the effector phase of the CD8 T-cell response to infection subsides. Strikingly, our results show that antibody prevents virus from seeding the skin and forming pock lesions, which are important for virus transmission between hosts.

scholarly journals Functional Analysis of the CD4+ T-Cell Response to Epstein-Barr Virus: T-Cell-Mediated Activation of Resting B Cells and Induction of Viral BZLF1 Expression

2000 ◽  
Vol 74 (14) ◽  
pp. 6675-6679 ◽  
Author(s):  
Zheng Fu ◽  
Martin J. Cannon
Keyword(s):  
Functional Analysis ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Lymphoproliferative Disorders ◽  
T Cell Response ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT In contrast to the major role played by Epstein-Barr virus (EBV)-specific CD8+ cytotoxic T-cell responses in immunosurveillance, recent studies have offered the apparently paradoxical suggestion that development of EBV-driven human B-cell lymphoproliferative disorders and tumors in SCID/hu mice is dependent on the presence of T cells, in particular CD4+ T cells. This study presents a functional analysis of the CD4+T-cell response to EBV and shows that while CD4+ T cells may be cytotoxic, they also express Th2 cytokines and CD40 ligand (gp39) and possess B-cell helper function. We show that EBV-specific CD4+ T cells can provide non-HLA-restricted help for activation of resting B cells via a gp39-CD40-dependent pathway and are able to induce expression of BZLF1, a viral lytic cycle transactivator in latently infected resting B cells, ultimately resulting in rapid outgrowth of transformed B-cell colonies. These results support the proposal that CD4+ T cells may play a key role in reactivation of latent EBV infection and may thus contribute to the pathogenesis of EBV-driven lymphoproliferative disorders.

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 An Optimized CD4 T-Cell Response Can Control Productive and Latent Gammaherpesvirus Infection

2004 ◽  
Vol 78 (13) ◽  
pp. 6827-6835 ◽  
Author(s):  
Rebecca L. Sparks-Thissen ◽  
Douglas C. Braaten ◽  
Scott Kreher ◽  
Samuel H. Speck ◽  
Herbert W. Virgin
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Acute Infection ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cd4 T Cell

ABSTRACT CD4 T cells are important for control of infection with murine gammaherpesvirus 68 (γHV68), but it is not known whether CD4 T cells function via provision of help to other lymphocyte subsets, such as B cells and CD8 T cells, or have an independent antiviral function. Moreover, under conditions of natural infection, the CD4 T-cell response is not sufficient to eliminate infection. To determine the functional capacities of CD4 T cells under optimal or near-optimal conditions and to determine whether CD4 T cells can control γHV68 infection in the absence of CD8 T cells or B cells, we studied the effect of ovalbumin (OVA)-specific CD4 T cells on infection with a recombinant γHV68 that expresses OVA. OVA-specific CD4 T cells limited acute γHV68 replication and prolonged the life of infected T-cell receptor-transgenic RAG (DO.11.10/RAG) mice, demonstrating CD4 T-cell antiviral activity, independent of CD8 T cells and B cells. Despite CD4 T-cell-mediated control of acute infection, latent infection was established in DO.11.10/RAG mice. However, OVA-specific CD4 T cells reduced the frequency of latently infected cells both early (16 days postinfection) and late (42 days postinfection) after infection of mice containing CD8 T cells and B cells (DO.11.10 mice). These results show that OVA-specific CD4 T cells have B-cell and CD8 T-cell-independent antiviral functions in the control of acute infection and can, in the absence of preexisting CD8 T-cell or B-cell immunity, inhibit the establishment of gammaherpesvirus latency.

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