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T Regulatory Cells – Friends or Foes?
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (GIG)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

T regulatory cells (Tregs) have been extensively studied in patients with cancer or autoimmunity. These cells hamper the immune system’s ability to clear tumor cells in cancer patients. In autoimmune diseases, on the other hand, they are not able to restrain autoreactive immune responses. If we manage to understand Tregs and their role in health and diseases we may be able to develop better immunomodulatory therapies.

Early studies demonstrated that tolerance was maintained by a subset of CD25+ T-cells. CD25 was the earliest marker for Tregs and is still often used to define these cells. Several Treg-associated markers have been suggested throughout the years. However, these markers can be upregulated by activated T-cells as well. The most specific marker for Tregs is currently the transcription factor forkhead box P3 (FoxP3).

In this thesis, we investigated the presence of CD25- Tregs in patients with B-cell malignancies and in patients with autoimmunity. These cells were identified in both patient groups. Further, patients with B-cell malignancies often have high levels of soluble CD25 (sCD25) in the periphery. In our patient cohorts, the level of peripheral Tregs correlated with the level of sCD25 in patients with lymphoma. Tregs were shown to release sCD25 in vitro and sCD25 had a suppressive effect on T-cell proliferation. These data show that Tregs may release CD25 to hamper T-cell proliferation and that this may be an immune escape mechanism in cancer patients.

Previous studies have demonstrated that an increased infiltration of FoxP3+ cells into lymphoma-affected lymph nodes is associated with a better patient outcome. This is in contrast to studies from non-hematological cancers where an increased presence of Tregs is associated with a poor prognosis. Since previous studies have shown that Tregs are able to kill B-cells, we wanted to investigate if Tregs are cytotoxic in patients with B-cell tumors. In the subsequent studies, Tregs from patients with B-cell lymphoma and B-cell chronic lymphocytic leukemia (CLL) were phenotyped to investigate the presence of cytotoxic markers on these cells. FoxP3-expressing T-cells from both patients with CLL and B-cell lymphoma displayed signs of cytotoxicity by upregulation of FasL and the degranulation marker CD107a. Tregs from CLL patients could further kill their autologous B-cells in in vitro cultures.

Taken together the studies in this thesis have demonstrated two possible new functions of Tregs in patients with B-cell malignancies and the presence of CD25- Tregs in both cancer and autoimmunity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2010. , p. 63
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 576
Keywords [en]
Treg, T regulatory cell, FoxP3, CD25, CLL, B-cell lymphoma
National Category
Immunology in the medical area
Research subject
Clinical Immunology
Identifiers
URN: urn:nbn:se:uu:diva-128837ISBN: 978-91-554-7843-8 (print)OAI: oai:DiVA.org:uu-128837DiVA, id: diva2:331874
Public defence
2010-09-10, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2010-08-19 Created: 2010-07-26 Last updated: 2018-01-12Bibliographically approved
List of papers
1. T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell malignancies
Open this publication in new window or tab >>T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell malignancies
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2010 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 131, no 3, p. 371-376Article in journal (Refereed) Published
Abstract [en]

Interleukin-2 (IL-2) is one of the most studied cytokines driving T-cell proliferation, activation and survival. It binds to the IL-2 receptor consisting of three chains, the alpha (CD25), beta and common gamma (gammac). The binding of the CD25 chain to IL-2 is necessary to expose high-affinity binding sites for the beta and gammac chains, which, in turn, are responsible for downstream signalling. A high level of soluble CD25 (sCD25) has been associated with a poor prognosis in patients with non-Hodgkin's lymphoma. The function and source of origin of this soluble receptor is not well investigated. In the present study we hypothesized that T regulatory (Treg) cells may release CD25 to act as a decoy receptor for IL-2, thereby depriving T-effector cells of IL-2. Peripheral blood from patients with B-cell malignancies (n = 26) and healthy controls (n = 27) was investigated for the presence and function of FoxP3(+) Treg cells and sCD25 by multi-colour flow cytometry and enzyme-linked immunosorbent assay. Further, the proliferative capacity of T cells was evaluated with or without the presence of recombinant sCD25. The results demonstrate that Treg cells from patients had lower CD25 expression intensity and that they released CD25 in vitro. Further, high levels of Treg cells correlated with sCD25 plasma concentration. Recombinant sCD25 could suppress T-cell proliferation in vitro. In conclusion, the release of sCD25 by Treg cells may be a mechanism to deprive IL-2 and thereby inhibit anti-tumour T-cell responses.

Keywords
B-cell malignancy, CD25, interleukin-2 receptor α, immune escape mechanism, T regulatory cell
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-128828 (URN)10.1111/j.1365-2567.2010.03308.x (DOI)000282690500008 ()20518821 (PubMedID)
Available from: 2010-07-26 Created: 2010-07-26 Last updated: 2017-12-12Bibliographically approved
2. T regulatory cells lacking CD25 are increased in MS during relapse
Open this publication in new window or tab >>T regulatory cells lacking CD25 are increased in MS during relapse
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2010 (English)In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 43, no 8, p. 590-597Article in journal (Refereed) Published
Abstract [en]

Dysregulation of inflammatory responses is considered to be a key element in autoreactive immune responses. T regulatory cells (Tregs) are important to maintain self-tolerance and the role of CD4(+)CD25(+)FoxP3(+) Tregs in autoimmunity has been extensively investigated. Recently, it was shown that Tregs in systemic lupus erythematosus lacked CD25 but were biologically functional. These data warrants for further investigation of CD25(- ) Tregs in human autoimmunity. We analyzed relapsing-remitting multiple sclerosis (MS) patients by multicolor flow cytometry for the expression of CD3, CD4, IL2R (CD25), FoxP3, and the IL7R (CD127). Further, the level of Tregs was compared in remitting and relapsing patients and correlated with disease duration. Patients in relapse exhibited higher levels of FoxP3-positive Tregs lacking CD25 compared to healthy controls (p < 0.05), indicating that Tregs attempt to restrain immune activity during relapse. The proportion of Tregs tended to be decreased with disease duration, while CD25(+)CD4(+) and CD25(+)CD8(+) effector T-cell proportions were elevated and positively correlated with overall disease duration (p < 0.05). In conclusion, while MS patients in remission have normal levels of Tregs of different phenotype, relapsing patients show an increased proportion of systemic CD25(- )FoxP3(+) Tregs. With time, the proportion of Tregs decrease while effector T cells expand.

Keywords
MS, T regulatory cells, T cells, FoxP3, CD25
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-128829 (URN)10.3109/08916930903541190 (DOI)000284074300003 ()20370571 (PubMedID)
Available from: 2010-07-26 Created: 2010-07-26 Last updated: 2017-12-12Bibliographically approved
3. FoxP3+ T-Cells in Patients with B-Cell Chronic Lymphocytic Leukemia Express Cytolytic Markers and Kill Autologous B-Cells
Open this publication in new window or tab >>FoxP3+ T-Cells in Patients with B-Cell Chronic Lymphocytic Leukemia Express Cytolytic Markers and Kill Autologous B-Cells
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Recent reports indicate that infiltration of FoxP3+ cells into the tumor area may be associated with better overall survival of patients with B-cell malignancies, which is in contrast to patients with non-hematopoetic tumors. Here, we demonstrate a possible mechanism to these findings. Since the tumor cell in lymphoma originates from the immune system we hypothesized that FoxP3+ T regulatory cells (Tregs) may have a suppressive role in tumor progression in patients with B-cell malignancies.

Peripheral blood was collected from 14 patients with B-cell chronic lymphocytic leukemia (B-CLL) and their Tregs were evaluated for cytolytic markers such as FasL and CD107a. We found that both conventional Tregs (CD4+ FoxP3+CD127low T-cells) and FoxP3+CD127high T-cells were significantly increased in patients with B-CLL compared to healthy controls. Further, both groups of FoxP3+ cells displayed higher expression of the degranulation marker CD107a indicating perforin/granzyme release. A flow cytometry-based cytotoxicity assay demonstrated that purified Tregs  from both patients and healthy controls could kill autologous B-cells in vitro.

In conclusion, FoxP3+ T-cells in patients with CLL show effector phenotype and may be involved in tumor cell control by their natural capacity to kill B-cells.

Keywords
T regulatory cells, FoxP3, chronic lymphocytic leukemia, CD107a, effector Treg, cytotoxic Treg
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-128830 (URN)
Available from: 2010-07-26 Created: 2010-07-26
4. Peripheral T Lymphocytes, Including FoxP3+ T-Cells, Exhibit a Cytotoxic Phenotype in Patients with B-Cell Lymphoma
Open this publication in new window or tab >>Peripheral T Lymphocytes, Including FoxP3+ T-Cells, Exhibit a Cytotoxic Phenotype in Patients with B-Cell Lymphoma
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Recent studies have shown that high levels of FoxP3+ cells within lymphoma-affected lymph nodes are associated with a better outcome of patients with B-cell lymphoma. This finding is opposite to what has been seen in patients with solid non-hematopoietic tumors. In an attempt to better understand the role of FoxP3+ cell in lymphoma, we collected peripheral blood from 17 patients and determined the level of T regulatory cells (CD3+CD4+FoxP3+CD127low lymphocytes) and FoxP3+CD127high T-cells (CD3+CD4+FoxP3+CD127high lymphocytes). The two subgroups of FoxP3+ T-cells, as well as conventional FoxP3- T-cells, were further analyzed for presence of cytotoxic markers such as FasL and CD107a. Patient plasma was analyzed for the immunosuppressive cytokines IL-10 and TGF-β. Finally, the proliferative capacity of T-cells was assessed using Alamar Blue assay. In lymphoma patients, both FoxP3+ T-cells and conventional T-cells had elevated levels of cytotoxic markers. No significant increase in IL-10 or TGF-β was detected and most patient T-cells had a normal proliferative capacity. This is the first, to our knowledge, study showing a cytotoxic phenotype of FoxP3+ T-cells in patients with B-cell lymphoma.

Keywords
FoxP3, CD107a, FasL, B-cell lymphoma, T-cells, Treg
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-128831 (URN)
Available from: 2010-07-26 Created: 2010-07-26 Last updated: 2010-07-26

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