JAK1/2 Inhibition Suppresses T Cell Proliferation and Inflammatory Cytokine Production In An Allogeneic Setting and Ameliorates Graft-Versus-Host Disease (GvHD) In a Murine GvHD Model

Abstract Graft-versus-host-disease (GvHD) constitutes a severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In GvHD, tissue damage is mediated by pro-inflammatory cytokines. Cytokine responses are mediated by activated Janus kinases (JAKs). We hypothesized that JAK1/2 inhibition might reduce T effector cell responses and inflammatory cytokine production in an allogeneic system, thereby ameliorating GvHD. We established an allogeneic (major mismatch) cell culture system using naive BALB/c CD4+ CD62Lhigh T cells that were co-cultured with C57BL/6 (B6) bone marrow derived dendritic cells (DC). JAK 1/2 signaling was specifically blocked using the small molecule inhibitor Ruxolitinib (INCB018424). By using a 3H Thymidine proliferation assay, we found that Ruxolitinib was able to inhibit the proliferation of allogeneic CD4+ effector T cells. In our intracellular cytokine staining experiments Ruxolitinib was able to impair the differentiation of naïve T cells into IFN-gamma and IL17A-producing T effector cells. Both cytokines – IFN-gamma and IL-17A – have been linked to aggravated courses of GvHD severity. In vivo administration of Ruxolitinib signficantly reduced lethal GvHD after allo-HSCT in a murine major mismatch model. BALB/c recipient mice were irradiated and received C57BL/6 (B6) T cell depleted bone marrow along with CD4+ and CD8+ T cells. Animals that were treated with an oral gavage of Ruxolitinib twice daily displayed significantly lower serum levels of IFN-gamma, TNF-alpha, IL-10 and IL-12p70, lower histological and clinical GvHD scores and improved overall survival compared to the control group. By using luciferase-positive (luc+) CD4+ and CD8+ T cells, we were able to visualize and quantify T cell migration after GvHD induction. The recipient mice received luc+ T cells along with conventional T cell depleted bone marrow. We were able to detect the luc+ T cell signal with a bioluminescence imaging system. At day 9 after allogeneic bone marrow transplantation, migration of donor T cells to GvHD target sites was significantly reduced in Ruxolitinib treated mice compared to control mice. In summary, our data demonstrate that suppression of inflammatory cytokine responses by JAK1/2 inhibitors modulates T effector cell responses in an allogeneic setting and improves survival in a murine major mismatch GvHD model. These observations suggest that JAK1/2 inhibition might be used for the treatment of GvHD following allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

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Spontaneous CD4 and CD8 Memory T Cell Responses Against MUC1 and Carcinoembryonic Antigen in Bone Marrow of Multiple Myeloma Patients.

Blood ◽

10.1182/blood.v110.11.3533.3533 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3533-3533

Author(s):

Mathias Witzens-Harig ◽

Dirk Hose ◽

Michael Hundemer ◽

Simone Juenger ◽

Anthony D. Ho ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

T Cells ◽

T Cell ◽

Carcinoembryonic Antigen ◽

Cd8 T Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Cell Responses

Abstract Introduction: The bone marrow (BM) is a site of induction of tumour antigen specific T cell responses in many malignancies. We have demonstrated in the BM of myeloma patients high frequencies of spontaneously generated CD8 memory T cells with specificity for the myeloma-associated antigen MUC1, which were not detectable in the peripheral blood (PB). Besides MUC1, carcinoembryonic antigen was recently identified as a tumour-associated antigen in a patient with multiple myeloma. Up to now, spontaneous CD4 T cell responses against myeloma-associated antigens have not been reported. We undertook this study to evaluate to what extent spontaneous CD4 T cell responses against myeloma antigens occur during myeloma progression and if MUC1 or carcinoembryonic antigen represent immunogenic targets of spontaneous CD4 and CD8 T cell responses. Methods: Altogether, 78 patients with multiple myeloma were included into the study. Presence of functionally competent antigen specific T cells was evaluated by ex vivo short term (40 h) IFN-γ Elispot analyses. CD4 T cell responses against MUC1 were assessed by stimulation of purified CD4 T cell fractions with antigen pulsed, autologous dendritic cells (DCs) pulsed with two synthetic 100 meric polypeptides (pp1-100ss and (137–157)5 tr) that can be processed and presented via multiple HLA-II alleles. CD4- or CD8 T cell reactivity against carcinoembryonic antigen was assessed on purified CD4- and CD8 T cell fractions by pulsing DCs with highly purified CEA derived from culture supernatants of an epithelial carcinoma cell line. CD8 responses against MUC1 were analyzed by stimulation of HLA-A2+ patients derived purified T cells with DCs loaded with HLA-A2 restricted MUC1-derived nonameric peptide LLLLTVLTV. As negative control antigen for MUC1 polypeptides and CEA human IgG was used for pulsing DCs at identical concentrations while HLA-A2-restricted peptide SLYNTVATL derived from HIV was used as control antigen for LLLLTVLTV. Test antigen specific reactivity was defined by significantly increased numbers of IFN-γ spots in triplicate test wells compared to control wells (p<0.05, students T test). Results: 8 out of 19 tested patients (42%) contained MUC1 specific CD8 T cells in their bone marrow, while MUC1 specific CD4 T cells were detected in the BM of 30% of the cases (3/10). Interestingly, in peripheral blood (PB) CD8 reactivity against MUC1 was detectable in only 1 out of 10 patients while CD4 reactivity in PB was not detectable at all (0/10). CEA was specifically recognized by BM CD8 T cells from 5 out of 30 patients (17%) and by BM CD4 T cells from 5 out of 18 patients (28%). CEA was not recognized by CD4 and CD8 T cells in the PB of the same patients (0/13). Conclusion: Spontaneous T helper responses against tumour-associated antigens occur in the BM at similar levels as antigen specific CD8 T cells responses while they are virtually undetectable in the PB. Compared to CEA, MUC1 induces CD8 T cell responses in a much higher proportion of myeloma patients. Nevertheless, our data suggest that CEA may trigger spontaneous T cell responses against multiple myeloma in a considerable number of patients. Thus, systematic functional analyses of this potential tumour antigen in multiple myeloma appears to be justified.

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EGCG, a Green Tea Catechin, reduces pro-inflammatory cytokine production by CD14+ Macrophages, Lymphocytic CD45+RO T cells, and mixed macrophage/T cell populations from IBD patients and controls.

Inflammatory Bowel Diseases ◽

10.1097/00054725-200812001-00083 ◽

2008 ◽

Vol 14 ◽

pp. S24

Author(s):

H Qazzaz ◽

R Fernandez ◽

M Linder ◽

M Bon-Homme ◽

W Tucker ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Green Tea ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Cell Populations ◽

Inflammatory Cytokine Production ◽

Green Tea Catechin

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Induction of Potentially Protective HIV-Specific T-Cell Responses In Vitro by Gag mRNA-Electroporated Dendritic Cells.

Blood ◽

10.1182/blood.v108.11.1261.1261 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1261-1261

Author(s):

Zwi N. Berneman ◽

Ellen R. Van Gulck ◽

Leo Heyndrickx ◽

Peter Ponsaerts ◽

Viggo F.I. Van Tendeloo ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cell Count ◽

Cd8 T Cells ◽

Peripheral Blood ◽

T Cell Responses ◽

Ifn Gamma ◽

Cell Responses ◽

Hiv 1

Abstract Human immunodeficiency virus type 1 (HIV-1) infection is characterized by dysfunction of HIV-1-specific T-lymphocytes. In order to suppress the virus and delay evolution to AIDS, antigen-loaded antigen-presenting cells, including dendritic cells (DC) might be useful to boost and broaden HIV-1-specific T-cell responses. Monocyte-derived DC from 15 untreated (“naive”) and 15 highly active anti-retroviral therapy (HAART)-treated HIV-1-infected patients were electroporated with codon-optimized (“humanized”) mRNA encoding consensus HxB-2 (hHxB-2) Gag protein. These DC were co-cultured for 1 week with autologous peripheral blood leucocytes (PBL). Potential expansion of specific T-cells was measured by comparing ELISPOT responses of PBL before and after co-culture, using a pool of overlapping peptides, spanning the HxB-2 Gag. Expansion of specific PBL after co-culture was noted for T cells producing interferon (IFN)-gamma, interleukin (IL)-2 and perforin (Wilcoxon signed rank test p<0.05, except for IL-2 in naive patients). From all HIV-1-seropositive persons tested, 12 HAART-treated and 12 naive patients match in absolute number of CD4+ T-cells. A comparison of the increase of the response between day 0 and after 1 week of stimulation between those two groups showed that the response was higher in HAART-treated subjects for IFN-gamma and IL-2 but not for perforin in comparison to untreated subjects. Examining purified CD4+ and CD8+ T-cells after co-culture revealed that HxB-2 Gag peptides induced IFN-gamma in both subsets, that IL-2 was only secreted by CD4+ T-cells and that perforin was dominantly secreted by CD8+ T-cells. Remarkably, the perforin response in the treatment-naive persons was negatively correlated with the peripheral blood absolute CD4+ and CD8+ T-cell count (respectively R=0.618, p=0.014; and R=0.529, p=0.043). Furthermore, the nadir absolute CD4+ T-cell count in HAART-treated subjects was positively correlated with the IL-2 response (R=0.521, p=0.046) and negatively correlated with the perforin response (R=0.588, p=0.021). In conclusion, DC from HAART-treated and therapy-naive subjects, electroporated with hHxB-2 gag mRNA have the capacity to induce secondary T-cell responses. In an earlier study (Van Gulck ER et al. Blood2006;107:1818–1827), we already demonstrated ex vivo that CD4+ and CD8+ T-cells from non-treated HIV-1-infected subjects can be directly triggered by DC electroporated with autologous proviral-derived gag mRNA. Taken together, our results open the perspective for a DC immunotherapy for HIV disease.

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PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGF-β Inhibitors

Blood ◽

10.1182/blood-2019-128182 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3241-3241

Author(s):

Minsuk Kwon ◽

Eui-Cheol Shin ◽

Yoon Seok Choi

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Cytokine Production ◽

Plasma Cells ◽

Myeloma Cells ◽

Tgf Β1

Programmed cell death (PD)-1/PD-Ligand 1(PD-L1) blockade that reinvigorates exhausted T cells has been approved for the treatment of various solid tumors and hematological malignancies. However, in a clinical trial of multiple myeloma (MM) patients, anti-PD-1 monotherapy did not result in a clinical response. Furthermore, clinical trials of combining PD-1 blockade with immunomodulatory drugs or anti-CD38 monoclonal antibody failed to demonstrate clinical benefits in MM patients. To overcome the limitation of anti-PD-1 therapy in MM, the phenotype and differentiation of CD8+ T cells need to be characterized in the bone marrow (BM) of MM patients, particularly by analyzing myeloma antigen-specific CD8+ T cells. In addition, the role of immunosuppressive factors abundant in the MM microenvironment should be considered, including TGF-β. First, we confirmed the upregulation of PD-1 and PD-L1 expression in CD8+ T cells and myeloma cells, respectively, from the BM of MM patients. PD-1-expressing CD8+ T cells from the BM of MM patients co-expressed other checkpoint inhibitory receptors including Tim-3, LAG-3, and TIGIT. We also investigated the expression of T-cell transcription factors, such as T-bet, and EOMES, which are related to T-cell differentiation. In BM from MM patients, PD-1+CD8+ T cells had a higher percentage of EomeshiT-betlo cells than PD-1-CD8+ T cells. These data demonstrate that PD-1-expressing CD8+ T cells from the BM of MM patients exhibit a terminally differentiated phenotype with co-expression of multiple immune checkpoint inhibitory receptors. These results were also observed in BM CD8+ T cells specific to myeloma antigens NY-ESO-1 and HM1.24. Next, we investigated proliferation and cytokine production of BM CD8+ T cells from MM patients. BM CD8+ T cells from MM patients exhibited reduced proliferation and cytokine production upon T cell receptor (TCR) stimulation, compared to BM CD8+ T cells from other control group such as of undetermined significance. However, both anti-PD-1 alone and combined blockade of PD-1 with other immune checkpoint receptors, such as Tim-3, Lag-3, or TIGIT, did not increase the proliferation of BM CD8+ T cells from MM patients. Likewise, anti-PD-1 treatment failed to induce reinvigoration of BM CD8+ T cells stimulated with HLA-A*0201-restricted myeloma antigen peptides, including NY-ESO-1157-165 and HM1.2422-30 peptides. These data demonstrate that blocking PD-1 is not sufficient to restore the function of BM CD8+ T cells from MM patients. It has been known that TGF-β, which is actively secreted by malignant plasma cells and BM stromal cells, can inhibit T-cell responses. We confirmed that the major source of TGF- β1 is plasma cells including myeloma cells among BMMCs from MM patients, and the number of TGF- β1-producing plasma cells, including myeloma cells, is increased in the BM of MM patients. We investigated whether blocking TGF-β signaling enhances reinvigoration of BM CD8+ T cells from MM patients. The combined blockade of PD-1 and TGF- β significantly increased the proliferation of BM CD8+ T cells from MM patients in the presence of TCR stimulation. The production of IFN-γ and TNF by BM CD8+ T cells was also rescued by combined blockade of PD-1 and TGF-β. Moreover, combination of anti-PD-1 antibody and TGF-β inhibitors increased proliferative responses of BM CD8+ T cells from HLA-A2+ MM patients stimulated with a mixture of HLA-A*0201-restricted myeloma antigen peptides (NY-ESO-1157-165 and HM1.2422-30 peptides). Thus, PD-1 blockade reinvigorates BM CD8+ T cells from MM patients in the presence of TGF-β inhibitors. Taken together, BM CD8+ T cells and myeloma antigen-specific CD8+ T cells express increased levels of PD-1 and have a terminally exhausted phenotype in MM patients. Under TGF-β inhibition, anti-PD-1 reinvigorates BM CD8+ T cells from MM patients, but PD-1 blockade alone does not restore the function of BM CD8+ T cells. Blocking both TGF-β and PD-1 can be a promising therapeutic strategy for the treatment of MM. Disclosures No relevant conflicts of interest to declare.

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Treatment of Antigen-Presenting Cells with Histone Deacetylase Inhibitors Represents a Novel Strategy To Overcome CD4+ T-Cell Tolerance: Divergent Effects on the IL10 and IL-12 Promoter.

Blood ◽

10.1182/blood.v106.11.2392.2392 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2392-2392

Author(s):

Hongwei Wang ◽

Fengdong Cheng ◽

P. Horna ◽

I.V. Suarez ◽

Jian Wu ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Inflammatory Cytokine ◽

T Cell Responses ◽

Cd4 T Cell ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Cell Responses ◽

Antigen Presenting

Abstract Tumor-antigen-specific T-cell tolerance imposes a significant barrier to the development of effective therapeutic cancer vaccines. Bone marrow-derived antigen presenting cells (APCs) are critical in the induction of this unresponsive state. The requirement for APCs in tolerance induction, together with their well-known role in priming T-cell antitumor responses place APCs at the crossroads of immune activation versus immune tolerance and points to manipulation of these cells as an enticing strategy to modulate T-cell responses against tumors. Identification of the intracellular mechanisms by which APCs induces either T-cell outcome represents therefore a critical step to better understand and overcome tumor-induced immune tolerance. Histones tail plays an important role in modulation of gene transcription. Emerging evidence suggest that inhibition of hystone deacetylases (HDAC) increases the expression of inflammatory genes. Given that the inflammatory status of the APC at the time of antigen presentation is central in determining T-cell priming versus T-cell tolerance, we evaluated the effects of the HDAC inhibitor LAQ842 (Novartis Pharmaceutical Inc.) on APC function and regulation of antigen-specific CD4+ T-cell responses. First, treatment of peritoneal elicited macrophages (PEM) or bone marrow derided dendritic cells (DCs) with increasing concentrations of LAQ842 resulted in enhanced acetylation of hystones H-2A, H-2B, H3 and H4. Analysis of the expression of MHC class molecules and co-stimulatory molecules revealed a significant increase in B7.2 and CD40 in LAQ842-treated APCs as compared to untreated APCs. Utilizing multi-template RNA probes and ELISA we found that LAQ842-treated APCs produce enhanced levels of several inflammatory mediators such as IL-1a, IL-1b, IL-6, TNF-a and RANTES relative to untreated APCs. Similarly, in response to LPS-stimulation, LAQ842-treated APCs produce significant higher levels of the pro-inflammatory cytokine IL-12 but reduce production of the anti-inflammatory cytokine IL-10 as determined by RT-PCR and ELISA. Furthermore, by chromatin immune precipitation (CHIP) assays we found that LAQ842-treated APCs display an increased acetylation of histones associated with the IL-12 promoter but a diminished acetylation of histones at the IL-10 promoter in response to LPS stimulation. Next, we evaluated whether the inflammatory APCs induced by LAQ842 were capable of effectively present antigen and prime productive antigen-specific T-cell responses. In vitro treatment of PEM or DCs with increasing concentrations of LAQ842 resulted in an enhanced presentation of HA-peptide to naïve CD4+ T cells specific for a MHC class II restricted epitope of influenza hemagglutinin (HA). Indeed, these clonotypic T cells display an enhanced HA-specific proliferation, IL-2 and IFN-gamma production relative to clonotypic T cells that encountered HA-antigen on untreated APCs. More importantly, LAQ842-treated APCs were able to restore the responsiveness of tolerant CD4+ T-cells isolated from lymphoma bearing hosts. By demonstrating that HDAC inhibitor induces inflammatory APCs capable of restoring the responsiveness of tolerant T-cells, our studies have unveiled a previously unknown immunological effect of these agents and have broadened their clinical scope as promising adjuvants in cancer immunotherapy.

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Remodeling Specific Immunity by Use of MHC-Tetramers Distinguishes Graft-Versus-Tumor Activity from Graft-Versus-Host-Disease.

Blood ◽

10.1182/blood.v106.11.1300.1300 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1300-1300

Author(s):

Barry J. Kappel ◽

Javier Pinilla-Ibarz ◽

Adam A. Kochman ◽

Jeffrey M. Eng ◽

Vanessa M. Hubbard ◽

...

Keyword(s):

Bone Marrow ◽

Immune Response ◽

T Cells ◽

T Cell ◽

Median Survival ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Cell Populations ◽

Host Disease ◽

Graft Versus Host

Abstract MHC molecules carrying selected peptides will bind specifically to their cognate T cell receptor on individual clones of reactive T cells. Fluorescently labeled, tetrameric MHC-peptide complexes have been widely used to detect and quantitate antigen specific T cell populations via flow cytometry. We hypothesized that such MHC-peptide tetramers could also be used to selectively deplete unique reactive T cell populations, while leaving the remaining T cell repertoire and immune response intact. We show in an MHC-matched, minor antigen disparate, murine BMT model (BALB.B → C57BL/6), MHC-peptide-tetramers can be used to deplete the T cells responsible for Graft-Versus-Host-Disease (GVHD), while leaving the remaining immune response intact, as demonstrated by the retention of Graft-Versus-Tumor (GVT) activity. Using PE-labeled tetramers, anti-PE microbeads and an autoMACs separation system, we successfully depleted donor splenocytes of alloantigen specific T cells prior to transplantation. We demonstrated the specificity of the depletion by showing loss of the tetramer reactivity after depletion, whereas no changes were observed in the Vβ repertoire and the percentage of T cells, B cells, NK cells, monocyte/macrophages and granulocytes between pre- and post-depletion samples. When analyzed 6 days after transplantation, mice receiving specifically-depleted splenocytes had <0.5% of their CD8+ T cells reactive against the alloantigen (tetramer +) as compared to >8.5% of the CD8+ T cells in mice that received control-depleted splenocytes. A nearly 50% decrease in in vivo proliferation of donor splenocytes, assessed by CFSE dilution, was seen 3 days after transplant in recipients of specifically-depleted splenocytes, as compared to mice receiving control-depleted splenocytes. However, pre- and post-depletion splenocytes (specific and control) were equally capable of mounting an immune response against third party cells as demonstrated by mixed lymphocyte reaction. In a series of bone marrow transplants designed to assess GVHD and GVT, mice receiving specifically-depleted splenocytes had a nearly 4-fold increased median survival due to significant decreases in GVHD morbidity and mortality compared to recipients of control-depleted splenocytes. All mice receiving splenocytes (tetramer-depleted or not) showed equal GVT activity. Finally, we were able to demonstrate the simultaneous abrogation of GVHD and the retention of GVT in a single bone marrow transplant. In recipients of specifically-depleted splenocytes, there was a 33% long-term survival and significant increases in median survival, as compared to recipients of non-depleted splenocytes, control-depleted splenocytes or bone marrow only; all of these latter groups succumbed to GVHD or tumor. This method also provides the proof-of-concept for similar strategies to selectively remove other unwanted T cell clones, which could result in novel therapies for certain autoimmune disorders, T cell malignancies and solid organ graft rejection.

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Carcinoembryonic-Antigen-Related Cell Adhesion Molecule (CEACAM) Expression on Multiple Myelomas Inhibits Their Recognition by Autologous Memory CD8 T Cells

Blood ◽

10.1182/blood.v112.11.738.738 ◽

2008 ◽

Vol 112 (11) ◽

pp. 738-738

Author(s):

Mathias Witzens-Harig ◽

Dirk Hose ◽

Michael Hundemer ◽

Simone Jünger ◽

Anthony D. Ho ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Plasma Cells ◽

Myeloma Cell ◽

Myeloma Cell Line ◽

Myeloma Cells ◽

Cell Responses ◽

Healthy Donors

Abstract Introduction. Previous studies clearly demonstrated the spontaneous induction and accumulation of functionally competent myeloma antigen–specific memory CD8 T cell responses in the bone marrow of a large proportion of myeloma patients. However, other studies convincingly demonstrated that CD8 T cells from myeloma patients were incabable of lysing autologous myeloma cells. An explanation for this apparent discrepancy is still lacking. CEACAMs are induced on T cells during TCR-specific activation and mediate a rapid blocking of T cell effector functions upon homophilic binding with CEACAMs expressed on target cells. We here addressed the question if myeloma cells might escape recognition by autologous, myeloma-specific CD8 T cells through CEACAM expression. Methods. Presence of myeloma-specific CD8 T cells was analyzed by IFN-y Elispot assays using separated, bone marrow derived CD8 T cells and myeloma-associated antigen-pulsed autologous DCs or autolgous myeloma cells as antigen presenting cells. Expression of CEACAMs 1–21 was analyzed by differential gene expression profiling of sorted CD138+ myeloma cells from bone marrow of 140 myeloma patients and of respective plasma cells from 14 healthy donors. In addition, the expression of CEACAMs 1, 5, 6 and 8 was analyzed by flowcytometry on the myeloma cell line MM8226 and on CD138+ myeloma cells from altogether 7 myeloma patients. A role of CEACAM on T cell recognition of autologous myeloma cells was analyzed by coculture of CD8 T cells and sorted, autologous myeloma cells in the presence or absence of blocking antibodies against CEACAMs by IFN-γ Elispot assay. Results. We identified the presence of myeloma-specifcic CD8 T cells in app. 40% of tested myeloma patients (N=20). However, in none of the tested cases T cells were able to directly recognize autologous myeloma cells. Over expression of CEACAM mRNA was found for CEACAM1, 6 and 8 in myeloma cells of up to 20% of patients, but not in plasma cells of healthy donors. Flowcytometric analysis revealed the protein expression of CEACAMs 1 and 6 on 25–50 % of the myeloma cells of all 7 tested patients and on the myeloma cell line MM8226. Blocking of CEACAMs on sorted myeloma cells before their coculture with autologous CD8 T cells resulted in significant T cell responses to myeloma cells in all tested patients (N=6), while in none of these cases the T cells were able to respond to unblocked myeloma cells. Conclusions. We here demonstrate for the first time the expression of CEACAMs 1 and 6 on freshly isolated myeloma cells. Blocking of these CEACAMs resulted in a spontaneous CD8 T cell response against cocultured autologous myeloma cells which was undetectable in case of unblocked CEACAM expression despite the presence of myeloma-reactive memory T cells. We suggest that CEACAMs on myeloma cells inhibit the re-activation of tumour antigen specific CD8 T cells upon interaction with myeloma cells and may contribute to the well characterized immune resistance of multiple myeloma.

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Contribution of CD8+ T cells to inflammatory cytokine production in systemic sclerosis (SSc)

Autoimmunity ◽

10.1080/08916934.2016.1217997 ◽

2016 ◽

Vol 49 (8) ◽

pp. 532-546 ◽

Cited By ~ 5

Author(s):

Matthias Klein ◽

Marc Schmalzing ◽

Giovanni Almanzar ◽

Sandrine Benoit ◽

Henning Hamm ◽

...

Keyword(s):

T Cells ◽

Systemic Sclerosis ◽

Cd8 T Cells ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Inflammatory Cytokine Production

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Bone Marrow NK1.1− and NK1.1+ T Cells Reciprocally Regulate Acute Graft versus Host Disease

Journal of Experimental Medicine ◽

10.1084/jem.189.7.1073 ◽

1999 ◽

Vol 189 (7) ◽

pp. 1073-1081 ◽

Cited By ~ 239

Author(s):

Defu Zeng ◽

David Lewis ◽

Sussan Dejbakhsh-Jones ◽

Fengshuo Lan ◽

Marcos García-Ojeda ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Peripheral Blood ◽

T Cell Subsets ◽

Host Disease ◽

Graft Versus Host ◽

Ifn Γ

Sorted CD4+ and CD8+ T cells from the peripheral blood or bone marrow of donor C57BL/6 (H-2b) mice were tested for their capacity to induce graft-versus-host disease (GVHD) by injecting the cells, along with stringently T cell–depleted donor marrow cells, into lethally irradiated BALB/c (H-2d) host mice. The peripheral blood T cells were at least 30 times more potent than the marrow T cells in inducing lethal GVHD. As NK1.1+ T cells represented <1% of all T cells in the blood and ∼30% of T cells in the marrow, the capacity of sorted marrow NK1.1− CD4+ and CD8+ T cells to induce GVHD was tested. The latter cells had markedly increased potency, and adding back marrow NK1.1+ T cells suppressed GVHD. The marrow NK1.1+ T cells secreted high levels of both interferon γ (IFN-γ) and interleukin 4 (IL-4), and the NK1.1− T cells secreted high levels of IFN-γ with little IL-4. Marrow NK1.1+ T cells obtained from IL-4−/− rather than wild-type C57BL/6 donors not only failed to prevent GVHD but actually increased its severity. Together, these results demonstrate that GVHD is reciprocally regulated by the NK1.1− and NK1.1+ T cell subsets via their differential production of cytokines.

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