scholarly journals Thyroid MALT lymphoma: self-harm to gain potential T-cell help

Leukemia ◽  
2021 ◽  
Author(s):  
Fangtian Wu ◽  
Natsuko Watanabe ◽  
Maria-Myrsini Tzioni ◽  
Ayse Akarca ◽  
Chunye Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Malt Lymphoma ◽  
Inflammatory Responses ◽  
Peripheral Tolerance ◽  
Activated T Cells ◽  
Genetic Changes ◽  
Self Harm ◽  
T Cell Help

AbstractThe development of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is driven by chronic inflammatory responses and acquired genetic changes. To investigate its genetic bases, we performed targeted sequencing of 93 genes in 131 MALT lymphomas including 76 from the thyroid. We found frequent deleterious mutations of TET2 (86%), CD274 (53%), TNFRSF14 (53%), and TNFAIP3 (30%) in thyroid MALT lymphoma. CD274 was also frequently deleted, together with mutation seen in 68% of cases. There was a significant association between CD274 mutation/deletion and TNFRSF14 mutation (p = 0.001). CD274 (PD-L1) and TNFRSF14 are ligands for the co-inhibitory receptor PD1 and BTLA on T-helper cells, respectively, their inactivation may free T-cell activities, promoting their help to malignant B-cells. In support of this, both the proportion of activated T-cells (CD4+CD69+/CD4+) within the proximity of malignant B-cells, and the level of transformed blasts were significantly higher in cases with CD274/TNFRSF14 genetic abnormalities than those without these changes. Both CD274 and TNFRSF14 genetic changes were significantly associated with Hashimoto’s thyroiditis (p = 0.01, p = 0.04, respectively), and CD274 mutation/deletion additionally associated with increased erythrocyte sedimentation rate (p = 0.0001). In conclusion, CD274/TNFRSF14 inactivation in thyroid MALT lymphoma B-cells may deregulate their interaction with T-cells, promoting co-stimulations and impairing peripheral tolerance.

scholarly journals Effects of blocking helper T cell induction in vivo with anti-Ia antibodies. Possible role of I-A/E hybrid molecules as restriction elements.

1980 ◽  
Vol 152 (4) ◽  
pp. 996-1010 ◽  
Author(s):  
J Sprent
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Activated T Cells ◽  
Hybrid Molecules ◽  
T Cell Help

To examine the role of Ia antigens in controlling T cell activation in vivo, unprimed (CBA X B6)F1 (H-2k X H-2b) T cells were positively selected to sheep erythrocytes (SRC) for 5 d in irradiated F1 mice in the presence of large doses of anti-Iak antibody. With selection in the presence of broad-spectrum anti-Iak antibody (A.TH anti-A.TL antiserum), the activated T cells were markedly reduced in their capacity to collaborate with either B10.BR (I-Ak I-Bk I-Jk I-Ek I-Ck) (kkkkk) or B10.A(4R) (kbbbb) B cells but gave good helper responses with B10 (bbbbb) and (B10 X B10.BR)F1 B cells. Because there was no evidence for suppression, these findings were taken to imply that the anti-Iak antibody bound to Ia determinants on radioresistant macrophagelike cells of F1 host origin and blocked the activation of the IGk-restricted subgroup of F1 T cells but did not affect activation of the Iab-restricted T cell subgroup. Analogous experiments in which F1 T cells were selected to SRC in F1 mice in the presence of monoclonal anti-I-Ak antibody gave different results. In this situation, the reduction in T cell help for Iak-bearing B cells applied to B10.A(4R) B cells but not to B10.BR B cells. With selection of F1 T cells in B10.A(4R) mice, by contrast, anti-I-Ak antibody blocked T cell help for both B10.A(4R) and B10.BR B cells. These data suggested that genes telomeric to the I-A subregion were involved in controlling T cell activation and T-B collaboration. Because no evidence could be found that I-B through I-C determinants per se could act as restrictions elements, the working hypothesis for the data is that Iak-restricted T cells consist of two subgroups of cells: one subgroup is restricted by I-A-encoded molecules, whereas the other is restricted by I-A/E hybrid molecules encoded by two separated genes situated in the I-A and I-E subregions, respectively. The notion that A/E hybrid molecules serve as restriction elements is in line with the findings of other workers that these molecules can act as alloantigens and control responses to certain antigens under double Ir gene control.

scholarly journals Prolonged activation of nasal immune cell populations and development of tissue-resident SARS-CoV-2 specific CD8 T cell responses following COVID-19

2021 ◽  
Author(s):  
Anna H.E. Roukens ◽  
Marion König ◽  
Tim Dalebout ◽  
Tamar Tak ◽  
Shohreh Azimi ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Nasal Mucosa ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Upper Airway ◽  
Effector Memory ◽  
Long Term Effects ◽  
Activated T Cells

AbstractThe immune system plays a major role in Coronavirus Disease 2019 (COVID-19) pathogenesis, viral clearance and protection against re-infection. Immune cell dynamics during COVID-19 have been extensively documented in peripheral blood, but remain elusive in the respiratory tract. We performed minimally-invasive nasal curettage and mass cytometry to characterize nasal immune cells of COVID-19 patients during and 5-6 weeks after hospitalization. Contrary to observations in blood, no general T cell depletion at the nasal mucosa could be detected. Instead, we observed increased numbers of nasal granulocytes, monocytes, CD11c+ NK cells and exhausted CD4+ T effector memory cells during acute COVID-19 compared to age-matched healthy controls. These pro-inflammatory responses were found associated with viral load, while neutrophils also negatively correlated with oxygen saturation levels. Cell numbers mostly normalized following convalescence, except for persisting CD127+ granulocytes and activated T cells, including CD38+ CD8+ tissue-resident memory T cells. Moreover, we identified SARS-CoV-2 specific CD8+ T cells in the nasal mucosa in convalescent patients. Thus, COVID-19 has both transient and long-term effects on the immune system in the upper airway.

scholarly journals Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e000967 ◽  
Author(s):  
Christopher A Chuckran ◽  
Chang Liu ◽  
Tullia C Bruno ◽  
Creg J Workman ◽  
Dario AA Vignali
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Modulation ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Standard Of Care ◽  
Peripheral Tolerance ◽  
Neuropilin 1

Checkpoint blockade immunotherapy established a new paradigm in cancer treatment: for certain patients curative treatment requires immune reinvigoration. Despite this monumental advance, only 20%–30% of patients achieve an objective response to standard of care immunotherapy, necessitating the consideration of alternative targets. Optimal strategies will not only stimulate CD8+ T cells, but concomitantly modulate immunosuppressive cells in the tumor microenvironment (TME), most notably regulatory T cells (Treg cells). In this context, the immunoregulatory receptor Neuropilin-1 (NRP1) is garnering renewed attention as it reinforces intratumoral Treg cell function amidst inflammation in the TME. Loss of NRP1 on Treg cells in mouse models restores antitumor immunity without sacrificing peripheral tolerance. Enrichment of NRP1+ Treg cells is observed in patients across multiple malignancies with cancer, both intratumorally and in peripheral sites. Thus, targeting NRP1 may safely undermine intratumoral Treg cell fitness, permitting enhanced inflammatory responses with existing immunotherapies. Furthermore, NRP1 has been recently found to modulate tumor-specific CD8+ T cell responses. Emerging data suggest that NRP1 restricts CD8+ T cell reinvigoration in response to checkpoint inhibitors, and more importantly, acts as a barrier to the long-term durability of CD8+ T cell-mediated tumor immunosurveillance. These novel and distinct regulatory mechanisms present an exciting therapeutic opportunity. This review will discuss the growing literature on NRP1-mediated immune modulation which provides a strong rationale for categorizing NRP1 as both a key checkpoint in the TME as well as an immunotherapeutic target with promise either alone or in combination with current standard of care therapeutic regimens.

scholarly journals Production and characterization of a bispecific IgG capable of inducing T-cell-mediated lysis of malignant B cells

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3343-3349 ◽  
Author(s):  
BK Link ◽  
GJ Weiner
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Hybridoma Cells ◽  
Activated T Cells ◽  
Human B Cells ◽  
B Cell Malignancy ◽  
Cell Malignancy

Abstract Bispecific monoclonal antibodies (bsabs) recognizing both CD3 and a tumor antigen can redirect T-cell-mediated cytotoxicity toward cells bearing that antigen. Such bsabs have been shown to be more effective than monospecific monoclonal antibodies (MoAbs) at preventing tumor growth in animal models of B-cell malignancy. The current studies describe the production and preliminary evaluation of a bsab designed to induce the lysis of malignant human B cells by human T cells. The bsab was obtained from a hybrid-hybridoma cell line produced by fusing OKT3-secreting hybridoma cells with hybridoma cells that secrete 1D10. 1D10 is an MoAb that recognizes an antigen found on a majority of malignant human B cells that has not been detected to a significant degree on normal resting or activated lymphocytes. High performance liquid chromatography (HPLC) was used to separate bsab from monospecific antibodies that were also present in the hybrid-hybridoma antibody product. The bsab was then evaluated in vitro for its ability to induce lysis of malignant B cells by activated T cells. The bsab consistently induced extensive lysis in vitro of 1D10 (+) cells, including both cell lines and cells obtained from patients with a variety of B-cell malignancies. No such effect was seen with activated T cells alone or activated T cells with monospecific antibody. No increased lysis was seen with 1D10 (-) cell lines. The bsab also mediated lysis of malignant B cells by autologous T cells. We conclude bsab containing an OKT3 arm and a 1D10 arm can induce T-cell-mediated lysis in a manner that is both potent and specific. This supports further evaluation of this bsab as a potential immunotherapy of B-cell malignancy.

scholarly journals Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Min Chen ◽  
Kumar Felix ◽  
Jin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Types ◽  
Activated T Cells ◽  
Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

Ex vivo–expanded DCs induce donor-specific central and peripheral tolerance and prolong the acceptance of donor skin grafts

Blood ◽  
2011 ◽  
Vol 117 (9) ◽  
pp. 2640-2648 ◽  
Author(s):  
Tomoyoshi Yamano ◽  
Sho Watanabe ◽  
Hiroyuki Hasegawa ◽  
Toshihiro Suzuki ◽  
Ryo Abe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Peripheral Tolerance ◽  
Skin Grafts ◽  
Major Histocompatibility ◽  
Clonal Deletion ◽  
Activated T Cells ◽  
Donor Skin ◽  
Major Histocompatibility Complexes

Abstract Dendritic cells (DCs) are known to regulate immune responses by inducing both central and peripheral tolerance. DCs play a vital role in negative selection of developing thymocytes by deleting T cells with high-affinity for self-peptide–major histocompatibility complexes. In the periphery, DCs mediate peripheral tolerance by promoting regulatory T-cell development, induction of T-cell unresponsiveness, and deletion of activated T cells. We studied whether allogeneic DCs, obtained from bone marrow cultured with either Flt3L (FLDCs) or granulocyte-macrophage colony-stimulating factor (GMDCs), could induce allospecific central and peripheral tolerance after IV injection; B cells were used as a control. The results showed that only FLDCs reached the thymus after injection and that these cells induced both central and peripheral tolerance to donor major histocompatibility complexes. For central tolerance, injection of FLDCs induced antigen-specific clonal deletion of both CD8 and CD4 single-positive thymocytes. For peripheral tolerance, injection of FLDCs induced donor-specific T-cell unresponsiveness and prolonged survival of donor-derived skin grafts. Tolerance induction by adoptive transfer of FLDCs could be a useful approach for promoting graft acceptance after organ transplantation.

scholarly journals CELL INTERACTIONS IN THE IMMUNE RESPONSE IN VITRO

1972 ◽  
Vol 136 (4) ◽  
pp. 737-760 ◽  
Author(s):  
Marc Feldmann
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Interaction ◽  
T And B Lymphocytes ◽  
Activated T Cells ◽  
Cell Cooperation

The mechanism of interaction of T and B lymphocytes was investigated in an in vitro hapten carrier system using culture chambers with two compartments separated by a cell impermeable nucleopore membrane. Because specific cell interaction occurred efficiently across this membrane, contact of T and B lymphocytes was not essential for cooperation which must have been mediated by a subcellular component or "factor." By using different lymphoid cell populations in the lower culture chamber and activated thymus cells in the upper chamber (with antigen present in both), it was found that the antigen-specific mediator acted indirectly on B cells, through the agency of macrophages. Macrophages which had been cultured in the presence of activated T cells and antigen acquired the capacity to specifically induce antibody responses in B cell-containing lymphoid populations. Trypsinization of these macrophages inhibited their capacity to induce immune responses, indicating that the mediator of cell cooperation is membrane bound. By using antisera to both the haptenic and carrier determinants of the antigen as blocking reagents, it was demonstrated that the whole antigen molecule was present on the surface of macrophages which had been exposed to activated T cells and antigen. Because specifically activated T cells were essential a component of the antigen-specific mediator must be derived from these cells. By using anti-immunoglobulin sera as inhibitors of the binding of the mediator to macrophages, the T cell component was indeed found to contain both κ- and µ-chains and was thus presumably a T cell-derived immunoglobulin. It was proposed that cell cooperation is mediated by complexes of T cell IgM and antigen, bound to the surface of macrophage-like cells, forming a lattice of appropriately spaced antigenic determinants. B cells become immunized by interacting with this surface. With this mechanism of cell cooperation, the actual pattern of antigen-B cell receptor interactions in immunization would be the same with both thymus-dependent and independent antigens. An essential feature of the proposed mechanism of cell cooperation is that macrophage-B cell interaction must occur at an early stage of the antibody response, a concept which is supported by many lines of evidence. Furthermore this mechanism of cell interaction can be elaborated to explain certain phenomena such as the highly immunogenic macrophage-bound antigen, antigenic competition, the distinction between immunity and tolerance in B lymphocytes, and the possible mediation of tolerance by T lymphocytes.

scholarly journals B-T Cell Interactions in GRAFT-Versus-Host Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 38-38
Author(s):  
Dhanya Kizhakayil ◽  
Abbirami Sathappan ◽  
Giusy Gentilcore ◽  
Zoltan Pos ◽  
Nikolett Lupsa ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cell Interactions ◽  
Peripheral Tolerance ◽  
P Value ◽  
3D Analysis ◽  
Immune Rejection ◽  
Mhc I

Cytotoxic T cells (CTLs) and B cells engage distinct interactions in GVHD patients' blood and tissues, detectable in regular flow-cytometry screenings, by size and by double positive CD19-CD8 antibody markers (Deola, BMT 2017). B-CTL couplets are formed by alpha-betaTCR+ CD8+ CTLs preferentially targeting CD27+ CD19+ cells displaying an activated CD80 and CD86 phenotype. Interactions may last from 5 minutes to roughly 1 hour, and release a pattern of T cell attracting chemokines, as IP10, MIG, ITAC, which are also known GVHD biomarkers. To further unravel the mechanism of this cell interaction, we built an in-vitro model where human PBMCs cells are expanded with cognate peptides and IL2 for 1-2 weeks, then immune-selected for CD8 antigen by Miltenyi microbeads negative-selection and incubated (2-18 hours) with fresh autologous CD19-B cells, immune-selected with the same method. The interactions are studied under confocal microscope video-imaging (Zeiss LSM 880+Imaris 3D analysis software) and in flow-cytometry (SymphonyA5 BD) after deep phenotype antibody staining. The intensity of interaction, measured by fluorescence interference on cell membranes, revealed an active engagement of CD19 and CD8 antigens. CD19 antigen penetrates deeper in contacting T cells, than CD8 on B cells, and consistently with this finding, after the interactions there is an antigen exchange between cells with CD19 antigen actively transferred in CD8 cells (p value =<0.001), but not the contrary. We already proved that this type of B-T interaction is not antigen specific in CTL-to-B direction (Deola et a, JI 2008) but to exclude cross-presentation from B to CTLs and to unravel the role of CD8, we interfered by antibody blocking of MHC class I pathway on B cells and CD8 on CTLs. B-T cell interactions are not abolished after MHC-I or CD8 blocking, the intensity of coupling is unchanged after MHC-I block, and is higher after blocking CD8 (p value=<0.001). In particular, by blocking CD8 molecule, T cells target preferentially CD19+/CD27- cells rather than CD19+/27+ cells. Interestingly, B cell engagement follows 2 repetitive patterns of interaction: a high intensity interaction that visually corresponds to tight coupling cells with high CD19 penetration in T cells, and a low-intensity continuous interaction, visually measurable by cells "sniffing" each other. Both patterns correspond to diverse Calcium flux activation on T cells and B cells, suggesting functional different pathways triggered by the 2 type of interactions. Deep phenotype flow cytometry analyses after coupling reveals distinct programs triggered by the contact in both B cells and T cells. While after the interaction CTLs double their pool of perforin bearing effectors and their fraction of CD45RA-/CD27+ memory CTLs, CD19 preferentially undergo a deletion of IgD- CD27- (DN) cells (13,85%+/-1,1 and 22,95%+/-4,5 CD95/Fas+, respectively in B cells alone and B+CTLs, n=2) and a rescue of affinity mature CD27+ IgD- cells (39.8%+/-25,47 and 21,2%+/- 29% CD95/Fas+ in the same groups) CTLs are the ultimate line of "tissue attack" in GVHD and several diseases, as autoimmune diseases, cancer, viral diseases, sharing a common pathological program definable as "immune rejection". B cells are key players in immune rejection, but a link between these 2 types of cells is still unclear. Our findings enforce the hypothesis of a program of peripheral tolerance/activation triggered directly between B cells and activated CTLs in the context of inflammation and of GVHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals T cell-dependent induction of NF-kappa B in B cells.

1993 ◽  
Vol 177 (4) ◽  
pp. 1215-1219 ◽  
Author(s):  
A C Lalmanach-Girard ◽  
T C Chiles ◽  
D C Parker ◽  
T L Rothstein
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Intracellular Signaling ◽  
Cell Interaction ◽  
Soluble Form ◽  
Nf Kappa B ◽  
Activated T Cells ◽  
Cell Stimulation

In comparison to B cell stimulation mediated by surface immunoglobulin (Ig) antigen receptor ligation, little is known about the intracellular events associated with T cell-dependent B cell responses. A model for the efferent phase of T cell-B cell interaction was used to examine the capacity of activated T cells to trigger nuclear expression of the trans-acting transcription factor, NF-kappa B, in B cells. Fixed, activated, but not fixed, resting Th2 cells were found to induce increased binding activity for a kappa B site-containing oligonucleotide in a time-dependent manner. This induction of NF-kappa B was eliminated by an antibody directed against a 39-kD cell interaction protein on activated T cells as well as by a soluble form of B cell CD40. Of particular relevance to intracellular signaling, NF-kappa B induction was not diminished by prior depletion of B cell protein kinase C (PKC) with phorbol myristate acetate. These results strongly suggest that T cell-dependent B cell stimulation is associated with NF-kappa B induction via p39-CD40 interaction and that this is brought about by non-PKC dependent signaling, in marked contrast to the previously documented requirement for PKC in sIg receptor-mediated stimulation. This suggest that NF-kappa B responds to more than one receptor-mediated intracellular signaling pathway in B cells and may be part of a "final common pathway" for B cell stimulation.

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