The role of human regulatory T cells in controlling immune responses

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

Regulatory T cells (Tregs) form a subpopulation of approximately 5–10% of CD4+ T cells. The best marker for Tregs is the forkhead transcription factor P3 (FOXP3), which is essential for their development and function. In humans, functionally mature FOXP3+ Tregs are already found in the foetus at the beginning of the second trimester of pregnancy, but the kinetics of their maturation are not fully understood. In this thesis, we have studied the thymic production of Tregs in relation to their frequency in peripheral blood using flow cytometry and quantitative polymerase chain reaction (PCR). Our data indicate that the thymic output of human Tregs is very stable, but in the periphery, the increased proliferation and homeostasis of FOXP3+ Tregs, as well as the transient expression of FOXP3 by activated conventional cells, affect the level of FOXP3 expression. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare, recessively inherited autoimmune disease caused by mutations in the autoimmune regulator gene (AIRE), and provides a unique setup to study the pathogenesis of human autoimmunity. The loss of AIRE function impairs the deletion of autoreactive T cells in the thymus as well as the function of Tregs in the periphery. We showed that in APECED patients, the peripheral naïve recent thymic emigrant (RTE) Tregs are rapidly dividing and decreased in numbers compared with healthy individuals. Furthermore, the patients’ activated Tregs express FOXP3 in substantially lower levels than those in healthy controls. To assess the origin of this defect in the activated Tregs in APECED patients, we used T cell receptor sequencing to analyse the clonal relationship between four T cell subsets in healthy controls and APECED patients. Activated and naïve subsets in Tregs and T helper cells were analysed, and the clonal sharing patterns were strikingly similar in patients and healthy controls. The naïve Tregs had only a minor overlap with the helper T cell subsets, supporting the distinction between these lineages in the thymus. The activated/memory Treg subset shared some clones with helper T cells, but mainly with the naïve Treg population. Our data give a more detailed view of the defect of Tregs in APECED patients, emphasising the role of impaired thymic selection.
Original languageEnglish
Supervisors/Advisors
  • Arstila, Petteri, Supervisor
Award date5 Dec 2018
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-4731-8
Electronic ISBNs978-951-51-4731-8
Publication statusPublished - 2018
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • T-Lymphocytes, Regulatory
  • Forkhead Transcription Factors
  • Receptors, Antigen, T-Cell
  • Hemorrhagic Fever with Renal Syndrome
  • +immunology
  • Polyendocrinopathies, Autoimmune
  • Candidiasis
  • Blood
  • Thymus Gland
  • Thymocytes
  • Autoimmunity
  • Self Tolerance
  • Major Histocompatibility Complex
  • T-Lymphocytes, Helper-Inducer
  • CTLA-4 Antigen
  • CD8-Positive T-Lymphocytes
  • CD4-Positive T-Lymphocytes
  • Down-Regulation
  • Up-Regulation
  • 3111 Biomedicine

Cite this

@phdthesis{c81e10f63aeb41ab8667af67356af277,
title = "The role of human regulatory T cells in controlling immune responses",
abstract = "Regulatory T cells (Tregs) form a subpopulation of approximately 5–10{\%} of CD4+ T cells. The best marker for Tregs is the forkhead transcription factor P3 (FOXP3), which is essential for their development and function. In humans, functionally mature FOXP3+ Tregs are already found in the foetus at the beginning of the second trimester of pregnancy, but the kinetics of their maturation are not fully understood. In this thesis, we have studied the thymic production of Tregs in relation to their frequency in peripheral blood using flow cytometry and quantitative polymerase chain reaction (PCR). Our data indicate that the thymic output of human Tregs is very stable, but in the periphery, the increased proliferation and homeostasis of FOXP3+ Tregs, as well as the transient expression of FOXP3 by activated conventional cells, affect the level of FOXP3 expression. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare, recessively inherited autoimmune disease caused by mutations in the autoimmune regulator gene (AIRE), and provides a unique setup to study the pathogenesis of human autoimmunity. The loss of AIRE function impairs the deletion of autoreactive T cells in the thymus as well as the function of Tregs in the periphery. We showed that in APECED patients, the peripheral na{\"i}ve recent thymic emigrant (RTE) Tregs are rapidly dividing and decreased in numbers compared with healthy individuals. Furthermore, the patients’ activated Tregs express FOXP3 in substantially lower levels than those in healthy controls. To assess the origin of this defect in the activated Tregs in APECED patients, we used T cell receptor sequencing to analyse the clonal relationship between four T cell subsets in healthy controls and APECED patients. Activated and na{\"i}ve subsets in Tregs and T helper cells were analysed, and the clonal sharing patterns were strikingly similar in patients and healthy controls. The na{\"i}ve Tregs had only a minor overlap with the helper T cell subsets, supporting the distinction between these lineages in the thymus. The activated/memory Treg subset shared some clones with helper T cells, but mainly with the na{\"i}ve Treg population. Our data give a more detailed view of the defect of Tregs in APECED patients, emphasising the role of impaired thymic selection.",
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author = "Tuisku-Tuulia Koivula",
note = "M1 - 115 s. + liitteet",
year = "2018",
language = "English",
isbn = "978-951-51-4731-8",
publisher = "[T.-T. Koivula]",
address = "Finland",

}

The role of human regulatory T cells in controlling immune responses. / Koivula, Tuisku-Tuulia.

Helsinki : [T.-T. Koivula], 2018. 115 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - The role of human regulatory T cells in controlling immune responses

AU - Koivula, Tuisku-Tuulia

N1 - M1 - 115 s. + liitteet

PY - 2018

Y1 - 2018

N2 - Regulatory T cells (Tregs) form a subpopulation of approximately 5–10% of CD4+ T cells. The best marker for Tregs is the forkhead transcription factor P3 (FOXP3), which is essential for their development and function. In humans, functionally mature FOXP3+ Tregs are already found in the foetus at the beginning of the second trimester of pregnancy, but the kinetics of their maturation are not fully understood. In this thesis, we have studied the thymic production of Tregs in relation to their frequency in peripheral blood using flow cytometry and quantitative polymerase chain reaction (PCR). Our data indicate that the thymic output of human Tregs is very stable, but in the periphery, the increased proliferation and homeostasis of FOXP3+ Tregs, as well as the transient expression of FOXP3 by activated conventional cells, affect the level of FOXP3 expression. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare, recessively inherited autoimmune disease caused by mutations in the autoimmune regulator gene (AIRE), and provides a unique setup to study the pathogenesis of human autoimmunity. The loss of AIRE function impairs the deletion of autoreactive T cells in the thymus as well as the function of Tregs in the periphery. We showed that in APECED patients, the peripheral naïve recent thymic emigrant (RTE) Tregs are rapidly dividing and decreased in numbers compared with healthy individuals. Furthermore, the patients’ activated Tregs express FOXP3 in substantially lower levels than those in healthy controls. To assess the origin of this defect in the activated Tregs in APECED patients, we used T cell receptor sequencing to analyse the clonal relationship between four T cell subsets in healthy controls and APECED patients. Activated and naïve subsets in Tregs and T helper cells were analysed, and the clonal sharing patterns were strikingly similar in patients and healthy controls. The naïve Tregs had only a minor overlap with the helper T cell subsets, supporting the distinction between these lineages in the thymus. The activated/memory Treg subset shared some clones with helper T cells, but mainly with the naïve Treg population. Our data give a more detailed view of the defect of Tregs in APECED patients, emphasising the role of impaired thymic selection.

AB - Regulatory T cells (Tregs) form a subpopulation of approximately 5–10% of CD4+ T cells. The best marker for Tregs is the forkhead transcription factor P3 (FOXP3), which is essential for their development and function. In humans, functionally mature FOXP3+ Tregs are already found in the foetus at the beginning of the second trimester of pregnancy, but the kinetics of their maturation are not fully understood. In this thesis, we have studied the thymic production of Tregs in relation to their frequency in peripheral blood using flow cytometry and quantitative polymerase chain reaction (PCR). Our data indicate that the thymic output of human Tregs is very stable, but in the periphery, the increased proliferation and homeostasis of FOXP3+ Tregs, as well as the transient expression of FOXP3 by activated conventional cells, affect the level of FOXP3 expression. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare, recessively inherited autoimmune disease caused by mutations in the autoimmune regulator gene (AIRE), and provides a unique setup to study the pathogenesis of human autoimmunity. The loss of AIRE function impairs the deletion of autoreactive T cells in the thymus as well as the function of Tregs in the periphery. We showed that in APECED patients, the peripheral naïve recent thymic emigrant (RTE) Tregs are rapidly dividing and decreased in numbers compared with healthy individuals. Furthermore, the patients’ activated Tregs express FOXP3 in substantially lower levels than those in healthy controls. To assess the origin of this defect in the activated Tregs in APECED patients, we used T cell receptor sequencing to analyse the clonal relationship between four T cell subsets in healthy controls and APECED patients. Activated and naïve subsets in Tregs and T helper cells were analysed, and the clonal sharing patterns were strikingly similar in patients and healthy controls. The naïve Tregs had only a minor overlap with the helper T cell subsets, supporting the distinction between these lineages in the thymus. The activated/memory Treg subset shared some clones with helper T cells, but mainly with the naïve Treg population. Our data give a more detailed view of the defect of Tregs in APECED patients, emphasising the role of impaired thymic selection.

KW - T-Lymphocytes, Regulatory

KW - Forkhead Transcription Factors

KW - Receptors, Antigen, T-Cell

KW - Hemorrhagic Fever with Renal Syndrome

KW - +immunology

KW - Polyendocrinopathies, Autoimmune

KW - Candidiasis

KW - Blood

KW - Thymus Gland

KW - Thymocytes

KW - Autoimmunity

KW - Self Tolerance

KW - Major Histocompatibility Complex

KW - T-Lymphocytes, Helper-Inducer

KW - CTLA-4 Antigen

KW - CD8-Positive T-Lymphocytes

KW - CD4-Positive T-Lymphocytes

KW - Down-Regulation

KW - Up-Regulation

KW - 3111 Biomedicine

M3 - Doctoral Thesis

SN - 978-951-51-4731-8

PB - [T.-T. Koivula]

CY - Helsinki

ER -