scholarly journals Priming of MSCs with inflammation-relevant signals affects extracellular vesicle biogenesis, surface markers, and modulation of T cell subsets

2020 ◽  
Author(s):  
Seth Andrews ◽  
Ty Maughon ◽  
Ross Marklein ◽  
Steven Stice
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Low Cost ◽  
Extracellular Vesicle ◽  
Culture Conditions ◽  
T Cell Subsets ◽  
Necrosis Factor Alpha

AbstractAlthough considerable evidence exists supporting the use of mesenchymal stromal cells (MSCs) for treating immune diseases, successful clinical translation has been challenging and has led researchers to investigate cell-free alternatives. MSC-derived extracellular vesicles (MSC-EVs) have been shown to mediate a significant portion of the observed therapeutic effect, including immunosuppression. MSCs have been shown to respond to different aspects of the injury microenvironment such as inflammatory cytokines and hypoxia, although acidosis has not been investigated and different conditions have not been assessed in terms of their effects on MSC-EV function. This study investigated the effects of acidosis, hypoxia, and inflammatory cytokine priming on MSCs and MSC-EVs. We cultured MSCs in the presence of acidosis, hypoxia, or inflammatory cytokines (Interferon-gamma and Tumor Necrosis Factor-alpha) and compared the characteristics of their EVs as well as their uptake by and suppression of different T cell subsets. MSCs showed a greater effect on suppressing activated CD4+ and CD8+ T cells than MSC-EVs. However, MSC-EVs from MSCs primed with acidosis increased CD4+ and CD8+ regulatory T cell frequency in vitro. This functional response was reflected by MSC-EV uptake. MSC-EVs from acidosis-primed MSCs were taken up by CD4+ and CD8+ regulatory T cells at a significantly higher level than MSC-EVs from control, hypoxic, and inflammatory cytokine groups. These data suggest that a simple low-cost alteration in MSC culture conditions, acidosis, can generate extracelluar vesicles that have a desirable influence on anti inflammatory T cell subtypes.

696 Brentuximab vedotin, a CD30-directed antibody-drug conjugate, selectively depletes activated Tregs in vitro and in vivo

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A738-A738
Author(s):  
Bryan Grogan ◽  
Reice James ◽  
Michelle Ulrich ◽  
Shyra Gardai ◽  
Ryan Heiser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Efflux Pump ◽  
Apoptotic Cell ◽  
T Cell Subsets ◽  
Memory Cells ◽  
Antibody Drug Conjugate ◽  
Selective Depletion

BackgroundRegulatory T cells (Tregs) play an important role in maintaining immune homeostasis, preventing excessive inflammation in normal tissues. In cancer, Tregs hamper anti-tumor immunosurveillance and facilitate immune evasion. Selective targeting of intratumoral Tregs is a potentially promising treatment approach. Orthogonal evaluation of tumor-infiltrating lymphocytes (TILs) in solid tumors in mice and humans have identified CCR8, and several tumor necrosis family receptors (TNFRs), including TNFSFR8 (CD30), as receptors differentially upregulated on intratumoral Tregs compared to normal tissue Tregs and other intratumoral T cells, making these intriguing therapeutic targets.Brentuximab vedotin (BV) is approved for classical Hodgkin lymphoma (cHL) across multiple lines of therapy including frontline use in stage III/IV cHL in combination with doxorubicin, vinblastine, and dacarbazine. BV is also approved for certain CD30-expressing T-cell lymphomas. BV is comprised of a CD30-directed monoclonal antibody conjugated to the highly potent microtubule-disrupting agent monomethyl auristatin E (MMAE).The activity of BV in lymphomas is thought to primarily result from tumor directed intracellular MMAE release, leading to mitotic arrest and apoptotic cell death.The role CD30 plays in normal immune function is unclear, with both costimulatory and proapoptotic roles described. CD30 is transiently upregulated following activation of memory T cells and expression has been linked to highly activated/suppressive IRF4+ effector Tregs.MethodsHere we evaluated the activity of BV on CD30-expressing T cell subsets in vitro and in vivo.ResultsTreatment of enriched T cell subsets with clinically relevant concentrations of BV drove selective depletion of CD30-expressing Tregs > CD30-expressingCD4+ T memory cells, with minimal effects on CD30-expressing CD8+ T memory cells. In a humanized xeno-GVHD model, treatment with BV selectively depleted Tregs resulting in accelerated wasting and robust T cell expansion. The observed differential activity on Tregs is likely attributable to significant increases in CD30 expression and reduced efflux pump activity relative to other T cell subsets. Interestingly, blockade of CD25 signaling prevents CD30 expression on T cell subsets without impacting proliferation, suggesting a link between CD25, the high affinity IL-2 receptor, and CD30 expression.ConclusionsTogether, these data suggest that BV may have an immunomodulatory effect through selective depletion of highly suppressive CD30-expressing Tregs.AcknowledgementsThe authors would like to thank Michael Harrison, PharmD for their assistance in abstract preparation.Ethics ApprovalAnimals studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-024.

scholarly journals Quantitative assessment of the pool size and subset distribution of cytolytic T lymphocytes within human resting or alloactivated peripheral blood T cell populations.

1983 ◽  
Vol 158 (2) ◽  
pp. 571-585 ◽  
Author(s):  
A Moretta ◽  
G Pantaleo ◽  
L Moretta ◽  
M C Mingari ◽  
J C Cerottini
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Great Majority ◽  
T Cell Subsets ◽  
Cytolytic T Lymphocytes ◽  
Subset Distribution

In order to directly assess the distribution of cytolytic T lymphocytes (CTL) and their precursors (CTL-P) in the two major subsets of human T cells, we have used limiting dilution microculture systems to determine their frequencies. The two subsets were defined according to their reactivity (or lack thereof) with B9.4 monoclonal antibody (the specificity of which is similar, if not identical, to that of Leu 2b monoclonal antibody). Both B9+ and B9- cells obtained by sorting peripheral blood resting T cells using the fluorescence-activated cell sorter (FACS) were assayed for total CTL-P frequencies in a microculture system that allows clonal growth of every T cell. As assessed by a lectin-dependent assay, approximately 30% of peripheral blood T cells were CTP-P. In the B9+ subset (which represents 20-30% of all T cells), the CTL-P frequency was close to 100%, whereas the B9- subset had a 25-fold lower CTL-P frequency. It is thus evident that 90% and 10% of the total CTL-P in peripheral blood are confined to the B9+ or B9- T cell subsets, respectively. Analysis of the subset distribution of CTL-P directed against a given set of alloantigens confirmed these findings. CTL-P frequencies were also determined in B9+ and B9- subsets derived from T cells that had been activated in allogenic mixed leucocyte cultures (MLC). Approximately 10% of MLC T cells were CTL-P. This frequency was increased 3.5-fold in the B9+ subset, whereas the B9- subset contained only a small, although detectable number of CTL-P. Moreover, the great majority of the (operationally defined) CTL-P in MLC T cell population were found to be directed against the stimulating alloantigens, thus indicating a dramatic increase in specific CTL-P frequencies following in vitro stimulation in bulk cultures.

In vitro responses of human CD45R0brightRA− and CD45R0−RAbright T cell subsets and their relationship to memory and naive T cells

1997 ◽  
Vol 27 (9) ◽  
pp. 2383-2390 ◽  
Author(s):  
Joyce L. Young ◽  
Judith M. Ramage ◽  
J. S. Hill Gaston ◽  
Peter C. L. Beverley
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Subsets ◽  
Naive T Cells ◽  
Naïve T Cells

scholarly journals Phosphoantigen-activated Vγ2Vδ2 T cells antagonize IL-2–induced CD4+CD25+Foxp3+ T regulatory cells in mycobacterial infection

Blood ◽  
2009 ◽  
Vol 113 (4) ◽  
pp. 837-845 ◽  
Author(s):  
Guangming Gong ◽  
Lingyun Shao ◽  
Yunqi Wang ◽  
Crystal Y. Chen ◽  
Dan Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treatment Regimen ◽  
T Regulatory Cells ◽  
Mycobacterial Infection ◽  
T Cell Subsets ◽  
Regulatory Cells ◽  
Ifn Γ ◽  
Vγ2vδ2 T Cells

Abstract Although Foxp3+ T regulatory cells (Tregs) are well documented for their ability to suppress various immune cells, T-cell subsets capable of counteracting Tregs have not been demonstrated. Here, we assessed phosphoantigen-activated Vγ2Vδ2 T cells for the ability to interplay with Tregs in the context of mycobacterial infection. A short-term IL-2 treatment regimen induced marked expansion of CD4+CD25+Foxp3+ T cells and subsequent suppression of mycobacterium-driven increases in numbers of Vγ2Vδ2 T cells. Surprisingly, activation of Vγ2Vδ2 T cells by adding phosphoantigen Picostim to the IL-2 treatment regimen down-regulated IL-2–induced expansion of CD4+CD25+Foxp3+ T cells. Consistently, in vitro activation of Vγ2Vδ2 T cells by phosphoantigen plus IL-2 down-regulated IL-2–induced expansion of CD4+CD25+Foxp3+ T cells. Interestingly, anti–IFN-γ–neutralizing antibody, not anti–TGF-β or anti–IL-4, reduced the ability of activated Vγ2Vδ2 T cells to down-regulate Tregs, suggesting that autocrine IFN-γ and its network contributed to Vγ2Vδ2 T cells' antagonizing effects. Furthermore, activation of Vγ2Vδ2 T cells by Picostim plus IL-2 treatment appeared to reverse Treg-driven suppression of immune responses of phosphoantigen-specific IFNγ+ or perforin+ Vγ2Vδ2 T cells and PPD-specific IFNγ+αβ T cells. Thus, phos-phoantigen activation of Vγ2Vδ2 T cells antagonizes IL-2–induced expansion of Tregs and subsequent suppression of Ag-specific antimicrobial T-cell responses in mycobacterial infection.

Control of spontaneous in vitro IgE synthesis by T cell subsets: Allogenetic suppression by suppresor T cells

1982 ◽  
Vol 69 (1) ◽  
pp. 157
Author(s):  
M.J. Kraemer ◽  
H.D. Ochs ◽  
C.T. Furukawa ◽  
R.J. Wedgwood
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Subsets ◽  
Ige Synthesis

scholarly journals Functional Analysis of Effector and Regulatory T Cells in a Parasitic Nematode Infection

2008 ◽  
Vol 76 (5) ◽  
pp. 1908-1919 ◽  
Author(s):  
Sebastian Rausch ◽  
Jochen Huehn ◽  
Dennis Kirchhoff ◽  
Justyna Rzepecka ◽  
Corinna Schnoeller ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Chronic Phase ◽  
T Cell Subsets ◽  
Interleukin 4 ◽  
Effector Memory ◽  
Parasitic Nematodes ◽  
Cell Reactivity

ABSTRACT Parasitic nematodes typically modulate T-cell reactivity, primarily during the chronic phase of infection. We analyzed the role of CD4-positive (CD4+) T effector (Teff) cells and regulatory T (Treg) cells derived from mice chronically infected with the intestinal nematode Heligmosomoides polygyrus. Different CD4+ T-cell subsets were transferred into naïve recipients that were subsequently infected with H. polygyrus. Adoptive transfer of conventional Teff cells conferred protection and led to a significant decrease in the worm burdens of H. polygyrus-infected recipients. Roughly 0.2% of the CD4+ T cells were H. polygyrus specific based on expression of CD154, and cells producing interleukin 4 (IL-4) and IL-13 were highly enriched within the CD154+ population. In contrast, adoptive transfer of Treg cells, characterized by the markers CD25 and CD103 and the transcription factor Foxp3, had no effect on the worm burdens of recipients. Further analysis showed that soon after infection, the number of Foxp3+ Treg cells temporarily increased in the inflamed tissue while effector/memory-like CD103+ Foxp+ Treg cells systemically increased in the draining lymph nodes and spleen. In addition, Treg cells represented a potential source of IL-10 and reduced the expression of IL-4. Finally, under in vitro conditions, Treg cells from infected mice were more potent suppressors than cells derived from naïve mice. In conclusion, our data indicate that small numbers of Teff cells have the ability to promote host protective immune responses, even in the presence of Treg cells.

Immunosupressive Property of Mesenchymal Stem Cells (MSCs) in Mixed Lymphocyte Reactions In Vitro.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4313-4313 ◽  
Author(s):  
Jianyong Li ◽  
Lijuan Meng ◽  
Yu Zhu ◽  
Hua Lu ◽  
Changgeng Ruan
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
T Cell Subsets ◽  
Bone Marrow Mscs ◽  
Human Bone Marrow Mscs ◽  
Mixed Lymphocyte Reactions ◽  
Activation Phase

Abstract Meesnchymal stem cells (MSCs) were successfully used in the prevention and treatment of graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. To further explore the immunosuppressive property of human bone marrow (MSCs) in alloantigen-induced mixed lymphocyte reactions (MLRs) in vitro, human bone marrow MSCs and lymphocytes were prepared from healthy volunteers. MSCs were expanded in vitro in Mesencult serum free media. MSCs were cocultured with one-way MLRs and bidirectional MLRs, responder cells were labeled with carboxyfluorescein diacetate- succinimidyl ester (CFSE) in bidirectional MLRs. Cell Counting Kit-8(CCK-8)kit was used in cell proliferation detection, T-cell subsets were analyzed by flow cytometry (FCM). The results showed that MSCs were positive for CD105, CD73, CD13, CD90 and were negative for hematopoietic cell markers. In one-way MLRs, MSCs down-regulated alloantigen-induced lymphocyte expansion in a dose-dependent and MHC-independend manner. In two-way MLRs, MSCs suppressed proliferation of CFSE positive cells. T cell subsets were changed: Th2 and Tc2 were down-regulated. Th2 was reduced from 1.70% to 0.65%, and Tc2 reduced from 1.10% to 0.47%, while Th1 and Tc1 were unaffected. T cells that became CD69+, which was an early activation marker, were significantly up-regulated from 7.14% to 26.12% and CD4+CD25+T regulatory cells (CD4+CD25+Tr) were up-regulated from 4.04% to 6.19%, which indicating that suppression did not interfere with activation phase of T cells and might be mediated by CD4+CD25+Tr partly. We conclede that MSCs down-regulated alloantigen-induced lymphocyte expansion. The immunosupressive effect might involve in post-activation phase of T cells. CD4+CD25+Tr might contribute to the suppressory activity of MSCs.

Prolonged Thrombocytopenia After Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) and Its Association with an Increase in CD8+ CX3CR1+ Cells in Bone Marrow.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3077-3077
Author(s):  
Xiao-hui Zhang ◽  
Guo-xiang Wang ◽  
Yan-rong Liu ◽  
Lan-Ping Xu ◽  
Kai-Yan Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Surface Expression ◽  
T Cell Subsets ◽  
Control Group ◽  
Hematopoietic Stem ◽  
Cell Counts

Abstract Abstract 3077 Background: Since prolonged thrombocytopenia (PT) is an independent risk factor for poor clinical outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the underlying mechanisms need to be understood in order to develop selective treatments. Previous studies1–4 have suggested that abnormalities in B cells may play a role in the pathogenesis of PT. However, abnormalities in B cells alone do not fully explain the complete pathogenic mechanisms of PT. Our previous studies5 showed that the frequency of megakaryocytes with a ploidy value ≤ 8N was significantly increased in patients who developed PT after allo-HSCT compared to the control group. Mechanisms concerning the megakaryocyte hypoplasia in PT after allo-HSCT are not well understood. Design and Methods: PT was defined as a platelet count ≤80 × 109/L for more than 3 months after HSCT, recovery of all other cell counts, and no apparent cause for thrombocytopenia, such as aGVHD, disease recurrence, CMV infection, or antiviral drug treatment at three months post-HSCT when all other blood cell counts had return to normal.5 We analyzed T cell subsets in bone marrow (BM) and peripheral blood (PB) from allo-HSCT recipients with and without PT (n = 23 and 17, respectively) and investigated the expression characteristics of homing receptors CX3CR1, CXCR4 and VLA-4 by flow cytometry. Futhermore, Mononuclear cells (MNCs) from PT patients and controls were cultured with and without autologous CD8+ T cells in vitro, and clarify the effect of activated CD8+ T cells on the ploidy and apoptosis of megakaryocytes in the bone marrow. Results: The results demonstrated that the percentage of CD3+ T cells in the BM was significantly higher in PT patients than the experimental controls (76.00 ± 13.04% and 57.49 ± 9.11%, respectively, P < 0.001), whereas this difference was not significant for the PB (71.01 ± 11.49% and 70.49 ± 12.89%, respectively, P = 0.911). While, some T cell subsets in the BM and PB from allo-HSCT recipients with PT were not significantly different from that of the experimental control group, such as CD8+ T cells, CD4+ T cells, CD4+ CD25bright T cells (regulatory T cells), CD44hi CD62Llo CD8+ T cells and naive T cells (CD11a+ CD45RA+). Furthermore, the surface expression of homing receptor CX3CR1 on BM T cells (64.16 ± 14.07% and 37.45 ± 19.66%, respectively, P < 0.001) and CD8+ T cells (56.25 ± 14.54% and 35.16 ± 20.81%, respectively, P = 0.036), but not in blood, were significantly increased in PT patients compared to controls. For these two groups of patients, the surface expression of CXCR4 and VLA-4 on T cells and CD8+ T cells from both BM and PB did not show significant differences. Through the study in vitro, we found that the activated CD8+ T cells in bone marrow of patients with PT might suppress apoptosis (MNC group and Co-culture group: 18.02 ± 3.60% and 13.39 ± 4.22%, P < 0.05, respectively) and Fas expression (MNC group and Co-culture group: 21.10 ± 3.93 and 15.10 ± 2.33, P <0.05, respectively) of megakaryocyte. In addition, megakaryocyte with a ploidy value ≤ 8N (MNC group: 40.03 ± 6.42% and 24.54 ± 4.31%, respectively, P < 0.05) was significantly increased in patients with PT compared to the control group. Conclusions: In conclusion, an increased surface expression of CX3CR1 on T cells may mediate the recruitment of CD8+ T cells into the bone marrow in patients with PT who received an allo-HSCT. Moreover, CD8+CX3CR1+ T cells, which can have significantly increased numbers in bone marrow of patients with PT, likely caused a reduction in the megakaryocyte ploidy, and suppressed megakaryocyte apoptosis via CD8+ T cell-mediated cytotoxic effect, possibly leading to impaired platelet production. Therefore, treatment targeting CX3CR1 should be considered as a reasonable therapeutic strategy for PT following allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

Cytokine and T-Cell Phenotypic Changes Upon In Vivo Ibrutinib Therapy For CLL – Targeting Both CLL Cells and The Tumor-Microenvironment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2856-2856 ◽  
Author(s):  
Carsten U Niemann ◽  
Angelique Biancotto ◽  
Betty Y. Chang ◽  
Joseph J. Buggy ◽  
J. Philip McCoy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
T Cell Activation ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
T Cell Subsets ◽  
Bcr Signaling ◽  
Pre Treatment

Abstract Introduction Proliferation of chronic lymphocytic leukemia (CLL) cells is highly dependent on the microenvironment. B-cell receptor (BCR) signaling and interactions of the tumor cells with elements of the tissue microenvironment including T cells and macrophages appear to be of particular importance (Burger et al, Blood 2009; Herishanu at al, Blood 2011; Bagnara at al, Blood 2011). The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib is highly effective in blocking BCR signaling and leads to impressive clinical responses in CLL (Byrd et al, NEJM 2013). BTK is a member of the TEC kinase family that also includes TEC, IL2-inducible T cell kinase (ITK), and BMX/ETK. BTK is not expressed in T cells; however ITK, which is expressed in T cells, is directly inhibited by ibrutinib, and the drug reduces cytokine secretion from activated T cells without inducing apoptosis (Herman et al, Blood, 2011). Here, we sought to determine the in vivo effect of ibrutinib on T cells and cytokine levels in CLL patients treated with single agent ibrutinib. Methods The effect of ibrutinib on T-cell subsets, T-cell activation, and cytokine profiles was assessed in 10 CLL patients treated with 420mg ibrutinib daily in an ongoing phase II trial (NCT01500733). Matched samples of viably frozen peripheral blood mononuclear cells obtained from patients pre-treatment and after 6 months on ibrutinib were analyzed by flow cytometry. Cytokine levels pre-treatment and on days 1, 28, months 2, and 6 on ibrutinib were measured in the same patients using the Milliplex human cytokine assay. Results Consistent with inhibition of BCR signaling in CLL cells, CCL3 and CCL4 serum levels were rapidly and significantly decreased by ibrutinib as described previously (Ponader et al, Blood, 2012). In addition, serum levels of a number of inflammatory cytokines including IL6, IL8, IFNg, and TNFα were decreased by > 50% by day 28 of ibrutinib treatment and remained so by 6 months. This is of specific interest as “pseudoexhausted” T cells from CLL patients were recently shown to secrete high amounts of IFNg, and TNFα (Riches et al, Blood 2013). Thus, the decreased levels of inflammatory cytokines may reflect a reversal of T cell “pseduoexhaustion”. Furthermore, the immunosuppressive cytokine IL10, a Th1-type cytokine that is secreted by CLL cells and activated T cells, was also rapidly and significantly reduced. These in vivo data are consistent with previous in vitro data showing decreased secretion of IL6 and IL10 from T cells upon exposure to ibrutinib (Herman et al, Blood, 2011). Thus, ibrutinib appears to reduce cytokine and chemokine secretion from both CLL and T cells resulting in an overall decrease in inflammatory cytokines. While absolute T-cell numbers showed little change on treatment, we found that ibrutinib reduced the frequency of activated CD4+ T cells (Table). Furthermore, for 3 out of 4 patients, the percentage of Ki67 positive T cells in the peripheral blood decreased on ibrutinib therapy (mean decrease 63%). The frequency of the Th17 T-cell subset was also diminished. Consistently, a decrease in serum levels of IL17 was seen in the two patients having detectable IL17 levels pre-treatment. While changes in the cytokine pattern (decrease in IFNg and IL10) might suggest inhibition of a Th1-type response, there was no change in the ratio of Th1 to Th2 T-cell subsets by immunophenotyping. Conclusions We here demonstrate a decrease in the levels of inflammatory cytokines and in T-cell activation in CLL patients treated with ibrutinib. Whether this is a direct consequence of BTK inhibition in B-cells or, at least in part, results from inhibition of T-cell signaling remains to be determined. Nevertheless, our data indicate that ibrutinib significantly alters the composition of the tumor microenvironment in CLL, affecting soluble as well as cellular elements. These effects may be important for clinical response and the development of combination therapies and therefore deserve further study. Supported by the Intramural Research Program of NHLBI. We thank our patients for participating and acknowledge Pharmacyclics for providing study drug. Disclosures: Off Label Use: Ibrutinib in chronic lymphocytic leukemia. Chang:Pharmacyclics: Employment, Equity Ownership. Buggy:Pharmacyclics: Employment, Equity Ownership.

scholarly journals Increased Activation and Oligoclonality of Peripheral CD8+ T Cells in the Chronic Human Helminth Infection Alveolar Echinococcosis

2002 ◽  
Vol 70 (3) ◽  
pp. 1168-1174 ◽  
Author(s):  
Burkhard J. Manfras ◽  
Stefan Reuter ◽  
Thomas Wendland ◽  
Peter Kern
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Alveolar Echinococcosis ◽  
Ex Vivo ◽  
Active Role ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
And Function

ABSTRACT Alveolar echinococcosis (AE) in humans is a chronic disease characterized by slowly expanding liver lesions. Cellular immunity restricts the spreading of the extracellular pathogen, but functional contributions of CD4+ and CD8+ T cells are not defined. Here we studied ex vivo the phenotype and function of circulating T-cell subsets in AE patients by means of flow cytometry, T-cell receptor spectratyping, and lymphocyte proliferation. AE patients with parasitic lesions displayed a significant increase of activation of predominantly CD8+ T cells compared to healthy controls and AE patients without lesions. In vitro, proliferative T-cell responses to polyclonal stimulation with recall antigens and Echinococcus multilocularis vesicular fluid antigen were sustained during chronic persisting infection in all AE patients. Only in AE patients with parasitic lesions did T-cell receptor spectratyping reveal increased oligoclonality of CD8+ but not CD4+ T cells, suggesting a persistent antigenic drive for CD8+ T cells with subsequent proliferation of selected clonotypes. Thus, our data provide strong evidence for an active role of CD8+ T cells in AE.

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