Immune Characteristics Associated with Lymphomatoid Granulomatosis and Outcome Following Treatment with Interferon-Alpha

Abstract Abstract 963 Lymphomatoid granulomatosis (LYG) is a rare angiocentric/angiodestructive EBV+ B-cell lymphoproliferative disorder. LYG has a spectrum of clinical aggressiveness and histological grading. Grading relates to the number of EBV-positive B-cells with grade I /II being usually polyclonal or oligoclonal and grade III monoclonal. Historical outcomes of patients treated with steroids and/or chemotherapy have been poor with median survivals of 14 months. We have shown that LYG is associated with reduced CD8+ and CD4+ T-cells, and hypothesized that patients have defective immune surveillance of EBV+ B-cells. We are investigating the use of interferon-alpha (IFα) for grade I/II disease and have characterized the maturation, exhaustion, and homeostatic potential of bulk and antigen-specific CD8 T-cells. Patients with grade III disease are treated with DA-EPOCH-R. Characteristics of 53 patients on study include male sex 68%; median age (range) 46 (17-67) and median ECOG P.S. 1 (0-3). Disease sites include lung 98%, CNS 38%, kidney 15%, skin 17% and liver 19%. LYG grades are I –30%, II-26% and III-44%. Prior treatment was none –28%, chemotherapy+/− R-34% and steroids alone – 40% of patients. Herein, we report the outcome of patients with grade I/II LYG treated with IFα. IFα was commenced at 7.5 MIU TIW and dose escalated until best response and then continued for 1 year. Of 31 patients with grade I/II LYG treated with IFα, 28 were evaluable for response. Of these, 17 (60%) achieved a complete remission and 6 (21%) patients progressed with grade III disease and received chemotherapy. Of 10 patients with CNS disease, 9 achieved a CR with IFα. At a median follow-up time of 5 years, the progression-free survival of grade I/II LYG was 56%. The median time to remission was 9 months (3-40) and median IFα dose was 20 MIUs (7-40). Median EBV viral loads at study entry were 18 copies/106 genome equivalents (0-22727) (normal<200). We looked at T-cell kinetics in patients who achieved complete remission and observed statistically significant recovery in both CD4 (p=0.034) and CD8 p=0.034) cells after interferonα. We were interested in further elucidating T-cell function and used polychromatic flow cytometry to characterize CD8 T-cells in the peripheral blood of patients before and after IFα. In 17 patient samples, cells were stained with peptide-MHC I (pMHCI) multimers directed against T-cells specific for epitopes from latent and lytic EBV proteins along with antibodies defining CD8 sub-populations. Influenza or cytomegalovirus-specific pMHCI multimers were controls. We observed no difference in the frequency of EBV specific CD8 T-cells in the blood of LYG patients compared to controls. However, CD27 and PD1 expression appeared to be altered in the bulk CD8+ T-cells and in selected EBV-specific populations in LYG patients; these changes were marginally significant. Following completion of IFα, expression of PD-1, CD27 and CD127 were at normal levels. Evidence from some LYG patients suggests that IL2 production by EBV-specific T-cells is lost during LYG, and normalized after therapy. Our results suggest that LYG, an EBV-associated disease, may arise in the setting of a global deficit in CD8 T-cells with selected defects in EBV-specific immunity that resolve with successful therapy. Disclosures: No relevant conflicts of interest to declare.

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Obligatory Requirement for Antibody in Recovery from a Primary Poxvirus Infection

Journal of Virology ◽

10.1128/jvi.00116-06 ◽

2006 ◽

Vol 80 (13) ◽

pp. 6339-6344 ◽

Cited By ~ 73

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.

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IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling

Blood ◽

10.1182/blood.v124.21.1413.1413 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1413-1413

Author(s):

Bernd Jahrsdörfer ◽

Christof Kaltenmeier ◽

Ali Gawanbacht ◽

Thamara Beyer ◽

Catharina Schütz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Cell Function ◽

Conflicts Of Interest ◽

Third Party ◽

Immunological Methods ◽

Regulatory B Cells ◽

T Helper ◽

Regulatory Phenotype

Abstract Recently, we and others found that B cells differentiate into regulatory B cells (Breg) in response to interleukin (IL-)21. Of note, the key characteristic of human IL-21-induced Breg is expression of the serine protease granzyme B (GrB), whereas murine Breg, which require both IL-21 and CD40 ligand (CD40L) for their induction, predominantly express the immunosuppressive cytokine IL-10. Using two different disease models and various immunological methods, we further characterized the conditions leading to Breg differentiation in humans. Here, we demonstrate that in humans CD40L determines whether IL-21 induces differentiation of B cells into plasma cells (CD40L presence) or into GrB+ Breg (CD40L absence), which can directly control T cell proliferation by GrB-dependent degradation of the T cell receptor z-chain. Furthermore, we show that GrB+ Breg are circulating at high frequencies in the peripheral blood of untreated, highly viremic HIV patients, but not in healthy subjects. Of note, HIV-infected CD4+ T cells express IL-21, but not CD40L, and induce a GrB+ regulatory phenotype in healthy third party B cells in vitro. Consequently, addition of CD40L multimers can compensate for this insufficient T helper cell function, resulting in increased plasma cell/Breg ratios. Moreover, we investigated a patient with a congenital defect of Nuclear-Factor-kappa-B-Essential-Modulator (NEMO), which is essential for normal CD40 signaling. Even in the presence of viral infections, when CD4+ T helper cells from such patients are highly activated with strong expression of IL-21, they are not able to establish sufficient antibody responses. Instead, we found this patient to almost exclusively harbor B cells with a regulatory phenotype including high basal levels of GrB. When untreated NEMO B cells were co-cultured with allogeneic T cells from a healthy third party donor, these T cells failed to proliferate and to survive in response to a 6-day stimulation with anti-CD3/CD28 antibodies, an effect not observed with B cells from healthy donors. Since NEMO B cells lack normal CD40 signaling, our findings unequivocally demonstrate that in contrast to murine Breg IL-21-dependent induction of human Breg can occur in a CD40-independent fashion. Disclosures No relevant conflicts of interest to declare.

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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.

Journal of Experimental Medicine ◽

10.1084/jem.152.5.1274 ◽

1980 ◽

Vol 152 (5) ◽

pp. 1274-1288 ◽

Cited By ~ 31

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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Serum-derived exosomes promote CD8+ T cells to overexpress PD-1, affecting the prognosis of hypopharyngeal carcinoma

Cancer Cell International ◽

10.1186/s12935-021-02294-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qian Gao ◽

Hui-Ting Liu ◽

Yu-Qin Xu ◽

Lin Zhang ◽

Yuan-Ru Liu ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Cd8 T Cells ◽

Poor Prognosis ◽

Cell Function ◽

Immune Escape ◽

Cd8 T Cell ◽

Serum Exosomes

Abstract Background Hypopharyngeal cancer (HPC) is associated with a poor prognosis and a high recurrence rate. Immune escape is one of the reasons for the poor prognosis of malignant tumors. Programmed cell death ligand 1 (PD-L1) and programmed cell death-1 (PD-1) have been shown to play important roles in immune escape. However, the role of PD-1/PD-L1 in HPC remains unclear. In this experiment, we investigated the effect of exosomes from HPC patient serum on CD8+ T cell function and PD-1/PD-L1 expression and, thus, on prognosis. We hope to provide guidance for the identification of new targets for HPC immunotherapy. Methods PD-1 and CD8 expression in 71 HPC tissues and 16 paracarcinoma tissues was detected by immunohistochemistry. Concurrently, the clinicopathological data of the patients were obtained to conduct correlation analysis. Exosomes were isolated from serum and then identified by Western blotting (WB), transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA). Flow cytometry was used to assess the activity of CD8+ T cells after exosome stimulation. The effects of exosomes on the ability of CD8+ T cells to kill FaDu cells were assessed by CCK-8 assay. The expression of IL-10 and TGF-β1 was measured by enzyme-linked immunosorbent assay (ELISA). PD-L1 expression in HPC tissue samples was evaluated by immunohistochemistry, and the relationship between PD-1/PD-L1 expression and prognosis was investigated with patient specimens. Results PD-1 expression was significantly upregulated on CD8+ T cells in tumor tissues compared with those in normal tissues. The overall survival (OS) and disease-free survival (DFS) of PD-1-overexpressing patients were decreased. Serum exosomes from patients can elevate PD-1 expression on CD8+ T cells and suppress their killing capacity and secretory function. The rate of positive PD-L1 expression was increased in HPC tissues compared with paracancerous tissues. The DFS and OS of the PD-1(+)-PD-L1(+) group were significantly lower than those of the PD-1(−)-PD-L1(−) group. Conclusion Our findings indicate that serum exosomes from HPC patients can inhibit CD8+ T cell function and that the PD-1-PD-L1 pathway plays an important role in the immune escape of HPC. Exosomes combined with immunotherapy may guide the treatment of patients with advanced disease in the future.

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CD4 T cell control primary measles virus infection of the CNS: Regulation is dependent on combined activity with either CD8 T cells or with B cells: CD4, CD8 or B cells alone are ineffective

Virology ◽

10.1016/j.virol.2006.01.050 ◽

2006 ◽

Vol 347 (1) ◽

pp. 234-245 ◽

Cited By ~ 33

Author(s):

Antoinette Tishon ◽

Hanna Lewicki ◽

Abegail Andaya ◽

Dorian McGavern ◽

Lee Martin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Virus Infection ◽

Cd8 T Cells ◽

Measles Virus ◽

Cd4 T Cell ◽

Cell Control

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Divergent Impact of Glucose Availability on Human Virus-Specific and Generically Activated CD8 T Cells

Metabolites ◽

10.3390/metabo10110461 ◽

2020 ◽

Vol 10 (11) ◽

pp. 461

Author(s):

Jenifer Sanchez ◽

Ian Jackson ◽

Katie R. Flaherty ◽

Tamara Muliaditan ◽

Anna Schurich

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Function ◽

Cd8 T Cell ◽

Cell Immune Response ◽

Complex Nature ◽

Human Virus ◽

Glucose Availability

Upon activation T cells engage glucose metabolism to fuel the costly effector functions needed for a robust immune response. Consequently, the availability of glucose can impact on T cell function. The glucose concentrations used in conventional culture media and common metabolic assays are often artificially high, representing hyperglycaemic levels rarely present in vivo. We show here that reducing glucose concentration to physiological levels in culture differentially impacted on virus-specific compared to generically activated human CD8 T cell responses. In virus-specific T cells, limiting glucose availability significantly reduced the frequency of effector-cytokine producing T cells, but promoted the upregulation of CD69 and CD103 associated with an increased capacity for tissue retention. In contrast the functionality of generically activated T cells was largely unaffected and these showed reduced differentiation towards a residency phenotype. Furthermore, T cells being cultured at physiological glucose concentrations were more susceptible to viral infection. This setting resulted in significantly improved lentiviral transduction rates of primary cells. Our data suggest that CD8 T cells are exquisitely adapted to their niche and provide a reminder of the need to better mimic physiological conditions to study the complex nature of the human CD8 T cell immune response.

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Anti–4-1bb Monoclonal Antibodies Abrogate T Cell–Dependent Humoral Immune Responses in Vivo through the Induction of Helper T Cell Anergy

Journal of Experimental Medicine ◽

10.1084/jem.190.10.1535 ◽

1999 ◽

Vol 190 (10) ◽

pp. 1535-1540 ◽

Cited By ~ 137

Author(s):

Robert S. Mittler ◽

Tina S. Bailey ◽

Kerry Klussman ◽

Mark D. Trailsmith ◽

Michael K. Hoffmann

Keyword(s):

Immune Response ◽

T Cells ◽

Monoclonal Antibodies ◽

T Cell ◽

B Cells ◽

Humoral Immunity ◽

Cd8 T Cells ◽

Immunodeficient Mice ◽

Humoral Immune

The 4-1BB receptor (CDw137), a member of the tumor necrosis factor receptor superfamily, has been shown to costimulate the activation of T cells. Here we show that anti–mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells. Injection of anti–4-1BB mAbs into mice being immunized with cellular or soluble protein antigens induced long-term anergy of antigen-specific T cells. The immune response to the type II T cell–independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed. Inhibition of humoral immunity occurred only when anti–4-1BB mAb was given within 1 wk after immunization. Anti–4-1BB inhibition was observed in mice lacking functional CD8+ T cells, indicating that CD8+ T cells were not required for the induction of anergy. Analysis of the requirements for the anti–4-1BB–mediated inhibition of humoral immunity revealed that suppression could not be adoptively transferred with T cells from anti–4-1BB–treated mice. Transfer of BALB/c splenic T cells from sheep red blood cell (SRBC)-immunized and anti–4-1BB–treated mice together with normal BALB/c B cells into C.B-17 severe combined immunodeficient mice failed to generate an anti-SRBC response. However, B cells from the SRBC-immunized, anti–4-1BB–treated BALB/c mice, together with normal naive T cells, exhibited a normal humoral immune response against SRBC after transfer, demonstrating that SRBC-specific B cells were left unaffected by anti–4-1BB mAbs.

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Potential Impact of B Cells on T Cell Function in Multiple Sclerosis

Multiple Sclerosis International ◽

10.1155/2011/423971 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Sara Ireland ◽

Nancy Monson

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

B Cells ◽

Cell Function ◽

The Central Nervous System ◽

Potential Impact ◽

Anti Cd20 ◽

The Impact ◽

Ms Pathogenesis

Multiple sclerosis is a chronic debilitating autoimmune disease of the central nervous system. The contribution of B cells in the pathoetiology of MS has recently been highlighted by the emergence of rituximab, an anti-CD20 monoclonal antibody that specifically depletes B cells, as a potent immunomodulatory therapy for the treatment of MS. However, a clearer understanding of the impact B cells have on the neuro-inflammatory component of MS pathogenesis is needed in order to develop novel therapeutics whose affects on B cells would be beneficial and not harmful. Since T cells are known mediators of the pathology of MS, the goal of this review is to summarize what is known about the interactions between B cells and T cells, and how current and emerging immunotherapies may impact B-T cell interactions in MS.

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Inhibition of normal B-cell function by human immunodeficiency virus envelope glycoprotein, gp120

Blood ◽

10.1182/blood.v79.5.1245.1245 ◽

1992 ◽

Vol 79 (5) ◽

pp. 1245-1254 ◽

Cited By ~ 20

Author(s):

N Chirmule ◽

N Oyaizu ◽

VS Kalyanaraman ◽

S Pahwa

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Function ◽

Cell Contact ◽

Cell Proliferation And Differentiation ◽

Cell Clones ◽

Glycoprotein Gp120

Abstract Despite the occurrence of hypergammaglobulinemia in human immunodeficiency virus (HIV) infection, specific antibody production and in vitro B-cell differentiation responses are frequently impaired. In this study, we have examined the effects of HIV envelope glycoprotein gp120 on T-helper cell function for B cells. In the culture system used, B-cell functional responses were dependent on T-B- cell contact, since separation of T and B cells in double chambers by Transwell membranes rendered the B cells unresponsive in assays of antigen-induced B-cell proliferation and differentiation. Cytokines secreted by T cells were also essential, since anti-CD3 monoclonal antibody (mAb)-activated, paraformaldehyde-fixed T-cell clones failed to induce B-cell proliferation and differentiation. Pretreatment of the CD4+ antigen-specific T cells with gp120 was found to impair their ability to help autologous B cells, as determined by B-cell proliferation, polyclonal IgG secretion, and antigen-specific IgG secretion. The gp120-induced inhibition was specific in that it was blocked by soluble CD4. Furthermore, only fractionated small B cells (which are T-cell-dependent in their function) manifested impaired responses when cultured with gp120-treated T cells. Antigen-induced interleukin (IL)-2 and IL-4, but not IL-6, secretion were markedly reduced in gp120-treated T-cell clones. Addition of exogenous cytokines failed to compensate for defective helper function of gp120-treated T cells. The findings in this study indicate that gp120 impairs helper functions of CD4+ T cells by interfering with T-B-cell contact- dependent interaction; the inhibitory effects of soluble envelope proteins of HIV may contribute to the immunopathogenesis of the HIV- associated disease manifestations.

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