Perforin Expressing CD4+T Cells Respond to CMV Antigens in CMV Seropositive Patients with B Cell Chronic Lymphocytic Leukaemia (B-CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4787-4787
Author(s):  
James Walton ◽  
Keirissa Lawson ◽  
Maria S. Manoussaka ◽  
Amit Nathwani ◽  
Vincent Emory ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cell Subset ◽  
Free Cell ◽  
Strong Increase ◽  
Cell Lysates ◽  
Cd69 Expression ◽  
Ifn Γ

Abstract Introduction: Perforin (PF) expressing CD4+ T cells are expanded in B-CLL patients [1] and are able to induce PF-mediated apoptosis of autologous leukaemic cells in the presence of bispecific anti-CD3/CD19 antibodies [2]. However, the role of the expanded PF+CD4+ T population in B-CLL remains unclear. In this study we have examined possible involvement of this cell subset in immune responses to cytomegalovirus (CMV). Methods: Blood mononuclear cells from 11 CMV seropositive (SP) and 6 seronegative (SN) B-CLL patients were cultured for 4 and 18 hours in presence of Downe cell lysates containing CMV-antigen or cell lysates alone (control) and brefeldin and co-stimulated with anti-CD28 and anti-CD49 monoclonal antibodies. Anti-CMV response was assessed by flow cytometry as percentages of CD69+ and IFNγ+ cells in PF+ and PF- CD4+T cell populations. Results: CD4+ T cells from 9 of 11 SP patients showed a strong increase in percentages of IFNγ+ cells after 18h, but not 4h, in culture with CMV antigens, compared to the control lysates and SN patients (Table) and healthy age-matched SP subjects (1.78±0.45, p=0.012). In contrast, none of the 6 SN patients as well as 2 out of 11 SP patients responded to CMV by increased IFNγ expression. In responders IFNγ+ cells were proportionally distributed between PF+ and PF- CD4+ T cells. High levels of cell activation measured by CD69 expression, especially in PF+ population, were mainly due to the Downe cell lysate since expression was significantly lower in lysate free cell cultures (8.3±11.5%, p=0.0018 for SP B-CLL patients). Anti-CMV response was accompanied by a decrease in percentages of CD4+PF+ cells suggesting antigen-induced degranulation. Conclusion: PF+CD4+ T cells respond to CMV antigens suggesting an expansion of mature CMV specific cytotoxic CD4+ T cells in the majority of CMV seropositive B-CLL patients. IFN-γ and CD69 expression by CD4+PF+ and PF- T cells after 18h exposure to CMV+ and CMV- lysates in CMV seropositive and seronegative B-CLL patients CD4+ PF+ CD4+ PF-CD4+ SN SP SN SP SN SP IFN- γ, % CMV+lys 0.7±0.58 9.1±7.9 2.0±3.0 p=0.013 14.4±13.6 0.61±0.56 p=0.008 9.0±8.1 CMV−lys 0.26±0.34 0.9±1.7 p=0.007 1.1±1.7 3.9±6.9 p=0.029 0.24±0.27 1.46±2.55 p=0.013 CD69+cells, % CMV+lys 16.3±14.2 21.4±13.0 41.9±35.1 51.2±30.3 14.9±13.4 20.4±13.2 CMV−lys 14.4±12.8 9.7±7.8 28.6±34.8 39.8±33.0 13.8±12.1 12.9±15.0

scholarly journals Broad phenotypic alterations and potential dysfunction of lymphocytes in individuals clinically recovered from COVID-19

2021 ◽  
Author(s):  
Jingyi Yang ◽  
Maohua Zhong ◽  
Ejuan Zhang ◽  
Ke Hong ◽  
Qingyu Yang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Cell Subset ◽  
Effector Memory ◽  
Peripheral Blood Mononuclear ◽  
Follicular Helper ◽  
Hla Dr ◽  
Ifn Γ

Abstract Although millions of patients have clinically recovered from COVID-19, little is known about the immune status of lymphocytes in these individuals. In this study, the peripheral blood mononuclear cells (PBMCs) of a clinically recovered (CR) cohort were comparatively analyzed with those of an age- and sex-matched healthy donor (HD) cohort. We found that CD8+ T cells in the CR cohort had higher numbers of effector T cells and effector memory T cells but lower Tc1 (IFN-γ+), Tc2 (IL-4+), and Tc17 (IL-17A+) cell frequencies. The CD4+ T cells of the CR cohort were decreased in frequency, especially the central memory T cell subset. Moreover, CD4+ T cells in the CR cohort showed lower PD-1 expression and had lower frequencies of Th1 (IFN-γ+), Th2 (IL-4+), Th17 (IL-17A+), and circulating follicular helper T (CXCR5+PD-1+) cells. Accordingly, the proportion of isotype-switched memory B cells (IgM−CD20hi) among B cells in the CR cohort showed a significantly lower proportion, although the level of the activation marker CD71 was elevated. For CD3−HLA-DR− lymphocytes in the CR cohort, in addition to lower levels of IFN-γ, granzyme B, and T-bet, the correlation between T-bet and IFN-γ was not observed. Additionally, by taking into account the number of days after discharge, all the phenotypes associated with reduced function did not show a tendency toward recovery within 4‒11 weeks. The remarkable phenotypic alterations in lymphocytes in the CR cohort suggest that SARS-CoV-2 infection profoundly affects lymphocytes and potentially results in dysfunction even after clinical recovery.

HCA587 protein vaccine induces specific antitumor immunity mediated by CD4+ T-cells expressing granzyme B in a mouse model of melanoma

2020 ◽  
Vol 20 ◽  
Author(s):  
Weiming Yang ◽  
Weiheng Zhang ◽  
Xiaozhong Wang ◽  
Liming Tan ◽  
Hua Li ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Antitumor Effect ◽  
Granzyme B ◽  
Cell Subset ◽  
Cell Mediated Immunity ◽  
Protein Vaccine ◽  
Tumor Tissues ◽  
Wide Range ◽  
Ifn Γ

Background: The antigen HCA587 (also known as MAGE-C2), which is considered a cancer-testis antigen, exhibits upregulated expression in a wide range of malignant tumors with unique immunological properties, and may thus serve as a promising target for tumor immunotherapy. Objective: To explore the antitumor effect of the HCA587 protein vaccine and the response of humoral and cell-mediated immunity. Methods: The HCA587 protein vaccine was formulated with adjuvants CpG and and ISCOM. B16 melanoma cells were subcutaneously inoculated to C57BL/6 mice, followed by treatment with HCA587 protein vaccine subcutaneously. Mouse survival was monitored daily, and tumor volume was measured every 2 to 3 days. The tumor sizes, survival time and immune cells in tumor tissues were detected. And the vital immune cell subset and effector molecules were explored. Results: After treatment with HCA587 protein vaccine, the vaccination generated elicited significant immune responses, which delayed tumor growth and improved animal survival. The vaccination increased the proportion of CD4+ T cells expressing IFN-γ and granzyme B in tumor tissues. Depletion of CD4+T cells resulted in an almost complete abrogation of the antitumor effect of the vaccination, suggesting that the antitumor efficacy was mediated by CD4+ T cells. In addition, knockout of IFN-γ resulted in a decrease in granzyme B levels which were secreted by CD4+ T cells, and the antitumor effect was also significantly attenuated. Conclusion: The HCA587 protein vaccine may increase the levels of granzyme B expressed by CD4+ T cells, and this increase is dependent on IFN-γ, and the vaccine resulted in a specific tumor immune response and subsequent eradication of the tumor.

Activation of Peripheral Blood T Cells by Interaction and Migration Through Endothelium: Role of Lymphocyte Function Antigen-1/Intercellular Adhesion Molecule-1 and Interleukin-15

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 886-896 ◽  
Author(s):  
David Sancho ◽  
Marı́a Yáñez-Mó ◽  
Reyes Tejedor ◽  
Francisco Sánchez-Madrid
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Cell Activation ◽  
Adhesion Molecule ◽  
Cell Activation ◽  
Cell Subset ◽  
Intercellular Adhesion Molecule ◽  
Lymphocyte Function ◽  
Ifn Γ

Abstract Cell adhesion molecules have a key role in the migration of T cells to inflammatory foci. However, the effect of the endothelial-lymphocyte interaction on the activation of the latter cells remains unresolved. We have studied the effect of resting and stimulated endothelial cells (ECs) on the activation of peripheral blood T cells (PBTLs), as assessed by the expression of CD69 and CD25 activation antigens. The incubation of PBTLs with tumor necrosis factor-–activated EC monolayers, either alive or fixed, induced the expression of CD69 but not CD25, preferentially in the CD8+CD45RO+ cell subset. Furthermore, it induced the production of cytokines such as IFN-γ, but not that of interleukin-2 (IL-2) and IL-4. EC treated with other stimuli such as IL-1β, IFN-γ, or lipopolysaccharide also showed the same proactivatory effect on T cells. Lymphocyte activation was almost completely inhibited by blocking anti-CD18 and anti–intercellular adhesion molecule-1 (anti–ICAM-1) monoclonal antibodies (MoAbs), but only slightly affected by MoAbs against CD49d, vascular cell adhesion molecule-1, and anti–IL-15. In addition, the interaction of PBTL with immobilized ICAM-1 induced CD69 expression in the same memory T-cell subset. IL-15 induced T-cell activation with expression of CD69 and CD25, and production of IFN-γ, and its effect was additive with that triggered by cell adhesion to either EC or immobilized ICAM-1. The transmigration of PBTLs through either confluent EC monolayers or ICAM-1–coated membranes also induced efficiently the expression of CD69. When IL-15 was used as chemoattractant in these assays, a further enhancement in CD69 expression was observed in migrated cells. Together these results indicate that stimulated endothelium may have an important role in T-cell activation, through the lymphocyte function antigen-1/ICAM-1 pathway, and that IL-15 efficiently cooperates in this phenomenon. These observations could account for the abundance of CD69+ cells in the lymphocytic infiltrates of several chronic inflammatory diseases.

Activation of Peripheral Blood T Cells by Interaction and Migration Through Endothelium: Role of Lymphocyte Function Antigen-1/Intercellular Adhesion Molecule-1 and Interleukin-15

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 886-896 ◽  
Author(s):  
David Sancho ◽  
Marı́a Yáñez-Mó ◽  
Reyes Tejedor ◽  
Francisco Sánchez-Madrid
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Cell Activation ◽  
Adhesion Molecule ◽  
Cell Activation ◽  
Cell Subset ◽  
Intercellular Adhesion Molecule ◽  
Lymphocyte Function ◽  
Ifn Γ

Cell adhesion molecules have a key role in the migration of T cells to inflammatory foci. However, the effect of the endothelial-lymphocyte interaction on the activation of the latter cells remains unresolved. We have studied the effect of resting and stimulated endothelial cells (ECs) on the activation of peripheral blood T cells (PBTLs), as assessed by the expression of CD69 and CD25 activation antigens. The incubation of PBTLs with tumor necrosis factor-–activated EC monolayers, either alive or fixed, induced the expression of CD69 but not CD25, preferentially in the CD8+CD45RO+ cell subset. Furthermore, it induced the production of cytokines such as IFN-γ, but not that of interleukin-2 (IL-2) and IL-4. EC treated with other stimuli such as IL-1β, IFN-γ, or lipopolysaccharide also showed the same proactivatory effect on T cells. Lymphocyte activation was almost completely inhibited by blocking anti-CD18 and anti–intercellular adhesion molecule-1 (anti–ICAM-1) monoclonal antibodies (MoAbs), but only slightly affected by MoAbs against CD49d, vascular cell adhesion molecule-1, and anti–IL-15. In addition, the interaction of PBTL with immobilized ICAM-1 induced CD69 expression in the same memory T-cell subset. IL-15 induced T-cell activation with expression of CD69 and CD25, and production of IFN-γ, and its effect was additive with that triggered by cell adhesion to either EC or immobilized ICAM-1. The transmigration of PBTLs through either confluent EC monolayers or ICAM-1–coated membranes also induced efficiently the expression of CD69. When IL-15 was used as chemoattractant in these assays, a further enhancement in CD69 expression was observed in migrated cells. Together these results indicate that stimulated endothelium may have an important role in T-cell activation, through the lymphocyte function antigen-1/ICAM-1 pathway, and that IL-15 efficiently cooperates in this phenomenon. These observations could account for the abundance of CD69+ cells in the lymphocytic infiltrates of several chronic inflammatory diseases.

scholarly journals Increased state of activation of CD4 positive T cells and elevated interferon γ production in pouchitis

Gut ◽  
1998 ◽  
Vol 43 (4) ◽  
pp. 499-505 ◽  
Author(s):  
A Stallmach ◽  
F Schäfer ◽  
S Hoffmann ◽  
S Weber ◽  
I Müller-Molaian ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Interferon Γ ◽  
Ileoanal Pouch ◽  
T Cell Subsets ◽  
Activation Markers ◽  
Ifn Γ

Background—Immunoregulatory abnormalities of T cells might be of importance in the pathogenesis of pouchitis after ileoanal pouch anastomosis (IAP).Aims—To characterise T cell subsets, their state of activation, and production of cytokines in inflamed and non-inflamed pouches in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP). The influence of T cell activation on mucosal transformation was also studied.Patients—Mucosal biopsy specimens were taken from 42 patients with IAP (33 with UC and nine with FAP).Methods—Mononuclear cells were isolated by standard techniques and characterised by three colour flow cytometry. Interferon γ (IFN-γ) production was studied using the ELISPOT technique.Results—In patients with UC with pouchitis there was a significant increase in the CD4:CD8 ratio, expression of activation markers on CD3+ cells, and number of IFNγ producing mononuclear cells compared with patients with UC without pouchitis (CD4:CD8 ratio 1.3 (range 0.7–2.7) versus 0.6 (0.1–1.0), p=0.012). In addition, a positive correlation between increased crypt depth and the number of CD4+ cells (r=0.57) was shown.Conclusion—The observed increase in activated mucosal CD4+ T cells and IFN-γ production might lead to mucosal destruction and crypt hyperplasia as seen in pouchitis.

scholarly journals The Role of β-Catenin in Th1 Immune Response against Tuberculosis and Profiles of Expression in Patients with Pulmonary Tuberculosis

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Kunlong Xiong ◽  
Jinxia Niu ◽  
Ruijuan Zheng ◽  
Zhonghua Liu ◽  
Yanzheng Song ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Cd4 T Cell ◽  
Cell Frequency ◽  
Tnf Α ◽  
Ifn Γ

β-Catenin is a key molecule of canonical Wnt/β-catenin pathway. Its roles and expression profiles in T cells of tuberculosis (TB) remain unclear. The aim of this study was to explore the role of β-catenin in CD4+ T cells and its expression characteristics in patients with pulmonary tuberculosis (PTB). In this study, CD4+ T cell-specific β-catenin conditional knockout mice (β-CAT-cKO mice) were aerosol infected with Mycobacteria tuberculosis (Mtb) H37RV with wild-type mice as controls. Four weeks after infection, the mRNA expression of IFN-γ, TNF-α, and TCF-7 in the lungs of mice was measured. CD4, CD8, β-catenin, IFN-γ, and TNF-α in mononuclear cells from the lungs and spleens were measured by flow cytometry, and the pathological changes of lungs were also observed. Patients with PTB were enrolled, with blood samples collected and PBMCs isolated. The expressions of β-catenin, IFN-γ, TNF-α, and PD-1 in CD4+ and CD8+ T cells were measured by flow cytometry. Results showed a decreased frequency of and reduced IFN-γ/TNF-α mRNA expression and secretion by CD4+ T cells in the lungs of infected β-CAT-cKO mice compared with infected wild-type controls, and only slightly more inflammatory changes were observed in the lungs. β-catenin expressions in CD4+ and CD8+ T cells were significantly decreased in blood cells of patients with severe PTB compared with those in mild PTB. The stimulation of peripheral blood mononuclear cells (PBMCs) with lithium chloride (LiCl), a stimulant of β-catenin, resulted in the increase in CD4+ T cell frequency, as well as their secretion of IFN-γ and TNF-α. β-Catenin demonstrated a moderately positive correlation with PD-1 in CD4+ T cells. β-Catenin along with PD-1 and IFN-γ in CD4+ T cells had a high correlation with those in CD8+ T cells. In conclusion, β-catenin may be involved in the regulation of Th1 response and CD4+ T cell frequency in TB.

scholarly journals Expansion, isolation and first characterization of bovine Th17 lymphocytes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Patricia Cunha ◽  
Yves Le Vern ◽  
Christophe Gitton ◽  
Pierre Germon ◽  
Gilles Foucras ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Free Cell ◽  
Protein Levels ◽  
Interleukin 17A ◽  
Th17 Lymphocytes ◽  
Ifn Γ ◽  
Bovine Species

Abstract Interleukin 17A-producing T helper cells (Th17) are CD4+ T cells that are crucial to immunity to extracellular bacteria. The roles of these cells in the bovine species are poorly defined, because the characterization of bovine Th17 cells lags behind for want of straightforward cultivation and isolation procedures. We have developed procedures to differentiate, expand, and isolate bovine Th17 cells from circulating CD4+ T cells of adult cows. Using polyclonal stimulation with antibodies to CD3 and CD28, we expanded IL-17A-positive CD4+ T cells in a serum-free cell culture medium supplemented with TGF-β1, IL-6 and IL-2. Populations of CD4+ T cells producing IL-17A or IFN-γ or both cytokines were obtained. Isolation of IL-17A-secreting CD4+ T cells was performed by labelling surface IL-17A, followed by flow cytometry cell sorting. The sorted Th17 cells were restimulated and could be expanded for several weeks. These cells were further characterized by cytokine profiling at transcriptomic and protein levels. They produced high amounts of IL-17A and IL-17F, and moderate amounts of IL-22 and IFN-γ. The techniques developed will be useful to characterize the phenotypic and functional properties of bovine Th17 cells.

scholarly journals Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection

2020 ◽  
Author(s):  
Cheleka A.M. Mpande ◽  
Virginie Rozot ◽  
Boitumelo Mosito ◽  
Munyaradzi Musvosvi ◽  
One B Dintwe ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Differentially Expressed ◽  
Cd4 T Cell ◽  
Remote Infection ◽  
Ifn Γ

AbstractBackgroundRecent Mycobacterium tuberculosis (M.tb) infection is associated with a higher risk of progression to tuberculosis disease, compared to persistent infection after remote exposure. However, current immunodiagnostic tools fail to distinguish between recent and remote infection. We aimed to characterise the immunobiology associated with acquisition of M.tb infection and identify a biomarker that can distinguish recent from remote infection.MethodsHealthy South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 months) and persistent (QuantiFERON-TB+ for >1.5 year) infection. We characterized M.tb-specific CD4 T cell functional (IFN-γ, TNF, IL-2, CD107, CD154), memory (CD45RA, CCR7, CD27, KLRG-1) and activation (HLA-DR) profiles by flow cytometry after CFP-10/ESAT-6 peptide pool or M.tb lysate stimulation. We then assessed the diagnostic performance of immune profiles that were differentially expressed between individuals with recent or persistent QuantiFERON-TB+.FindingsCFP-10/ESAT-6-specific CD4 T cell activation but not functional or memory phenotypes distinguished between individuals with recent and persistent QuantiFERON-TB+. In response to M.tb lysate, recent QuantiFERON-TB+ individuals had lower proportions of highly differentiated IFN-γ+TNF+ CD4 T cells expressing a KLRG-1+ effector phenotype and higher proportions of early differentiated IFN-γ-TNF+IL-2+ and activated CD4 T cells compared to persistent QuantiFERON-TB+ individuals. Among all differentially expressed T cell features CFP-10/ESAT-6-specific CD4 T cell activation was the best performing diagnostic biomarker of recent infection.InterpretationRecent M.tb infection is associated with highly activated and moderately differentiated functional M.tb-specific T cell subsets, that can be used as biomarkers to distinguish between recent and remote infection.

scholarly journals CD8low T cells expanded following acute Trypanosoma cruzi infection and benznidazole treatment are a relevant subset of IFN-γ producers

2020 ◽  
Vol 14 (12) ◽  
pp. e0008969
Author(s):  
Alessandro Marins-Dos-Santos ◽  
Bianca Perdigão Olivieri ◽  
Rafaella Ferreira-Reis ◽  
Juliana de Meis ◽  
Andrea Alice Silva ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Cell Subset ◽  
Effector Memory ◽  
Beneficial Effects ◽  
Effector Memory T Cells ◽  
Cd69 Expression ◽  
Pathogen Control ◽  
Ifn Γ

CD8 T cells are regarded as pivotal players in both immunoprotection and immunopathology following Trypanosoma cruzi infection. Previously, we demonstrated the expansion of CD8+ T lymphocytes in the spleen of T. cruzi-infected mice under treatment with benznidazole (N-benzyl-2-nitroimidazole acetamide; Bz), a drug available for clinical therapy. This finding underlies the concept that the beneficial effects of Bz on controlling acute T. cruzi infection are related to a synergistic process between intrinsic trypanocidal effect and indirect triggering of the active immune response. In the present study, we particularly investigated the effect of Bz treatment on the CD8+ T cell subset following T. cruzi infection. Herein we demonstrated that, during acute T. cruzi infection, Bz treatment reduces and abbreviates the parasitemia, but maintains elevated expansion of CD8+ T cells. Within this subset, a remarkable group of CD8low cells was found in both Bz-treated and non-treated infected mice. In Bz-treated mice, early pathogen control paralleled the lower frequency of recently activated CD8low cells, as ascertained by CD69 expression. However, the CD8low subset sustains significant levels of CD44highCD62Llow and CD62LlowT-bethigh effector memory T cells, in both Bz-treated and non-treated infected mice. These CD8low cells also comprise the main group of spontaneous interferon (IFN)-γ-producing CD8+ T cells. Interestingly, following in vitro anti-CD3/CD28 stimulation, CD8+ T cells from Bz-treated T. cruzi-infected mice exhibited higher frequency of IFN-γ+ cells, which bear mostly a CD8low phenotype. Altogether, our results point to the marked presence of CD8low T cells that arise during acute T. cruzi infection, with Bz treatment promoting their significant expansion along with a potential effector program for high IFN-γ production.

Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells

Blood ◽  
2005 ◽  
Vol 105 (7) ◽  
pp. 2821-2827 ◽  
Author(s):  
Sarah Glennie ◽  
Inês Soeiro ◽  
Peter J. Dyson ◽  
Eric W.-F. Lam ◽  
Francesco Dazzi
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Activation Markers ◽  
Ifn Γ

AbstractIt has been shown that mesenchymal stem cells (MSCs) induce T cells to become unresponsive. We characterized the phenotype of these T cells by dissecting the effect of MSCs on T-cell activation, proliferation, and effector function. For this purpose, an in vitro murine model was used in which T-cell responses were generated against the male HY minor histocompatibility antigen. In the presence of MSCs, the expression of early activation markers CD25 and CD69 was unaffected but interferon-γ (IFN-γ) production was reduced. The inhibitory effect of MSCs was directed mainly at the level of cell proliferation. Analysis of the cell cycle showed that T cells, stimulated in the presence of MSCs, were arrested at the G1 phase. At the molecular level, cyclin D2 expression was profoundly inhibited, whereas p27kip1 was up-regulated. When MSCs were removed from the cultures and restimulated with the cognate peptide, T cells produced IFN-γ but failed to proliferate. The addition of exogenous interleukin-2 (IL-2) did not restore proliferation. MSCs did not preferentially target any T-cell subset, and the inhibition was also extended to B cells. MSC-mediated inhibition induces an unresponsive T-cell profile that is fully consistent with that observed in division arrest anergy.

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