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On the induction and function of Foxp3+ regulatory T cells

Oderup, Cecilia LU (2006)
Abstract (Swedish)
Popular Abstract in Swedish

Vårt immunsystem har utvecklats för att skydda våra vävnader och organ vid infektioner, cancerväxt och andra skador. Immunsystemet utgörs av en mängd olika celltyper som på olika sätt specifikt, främst genom uttryck av receptorer på cellytan, reagerar på främmande strukturer, från t ex patogener eller tumör celler eller andra substanser som signalerar stress eller fara. Dessa signaler sätter igång kommunikationer mellan immunceller med olika uppgifter som i ett slutskede resulterar i effektiv eliminering av patogenen och läkning av den skadade vävnaden. En immunologisk reaktion inleds med rekrytering av de mer ospecifika delarna av immunsystemet, dessa utgörs bla av dendritiska celler, antigen... (More)
Popular Abstract in Swedish

Vårt immunsystem har utvecklats för att skydda våra vävnader och organ vid infektioner, cancerväxt och andra skador. Immunsystemet utgörs av en mängd olika celltyper som på olika sätt specifikt, främst genom uttryck av receptorer på cellytan, reagerar på främmande strukturer, från t ex patogener eller tumör celler eller andra substanser som signalerar stress eller fara. Dessa signaler sätter igång kommunikationer mellan immunceller med olika uppgifter som i ett slutskede resulterar i effektiv eliminering av patogenen och läkning av den skadade vävnaden. En immunologisk reaktion inleds med rekrytering av de mer ospecifika delarna av immunsystemet, dessa utgörs bla av dendritiska celler, antigen presenterande celler som genom ytreceptorer specifikt kan ta upp och bryta ned främmande ämnen, antigen som t ex bakterier för att sedan presentera dem på sin cellyta. Den mer specifika delen av immunsystemet består bla av T celler. Dessa uttrycker mer specifika antigen receptorer som har förmågan att binda och reagera på en enorm mängd olika strukturer. De dendritiska cellerna har som främsta uppgift att aktivera de mer specifika T cellerna vilket fungerar genom att T cellen specifikt binder antigen som presenteras på den dendritiska cellen. Denna interaktion leder till att T cellen och stimuleras att aktivera övriga delar av immunsystemet, för att sedan genom en gemensam respons döda patogenerna eller de infekterade cellerna.



Normalt aktiveras T cellerna endast av främmande ämnen, men det finns T celler som kan aktiveras mot kroppsegna strukturer. För att undvika autoimmuna reaktioner, immunsvar riktade mot den egna vävnaden och utveckling av sjukdomar som multipel skleros (MS), rheumatism eller insulinberoende diabetes maste dessa celler kontrolleras och hållas inaktiva. Denna avhandlig behandlar just denna reglering av autoimmuna T celler och främst funktionen hos de s k regulatoriska T cellerna som specifikt förhindrar aktiviteten hos de autoimmuna T cellerna. Vi har studerat hur de regulatoriska T cellerna påverkar de dendritiska cellerna och indirekt förhindrar aktiveringen av T celler. De regulatoriska T cellerna nedreglerar de för T cells aktivering essentiella ytreceptorerna CD80 och CD86. Vi har har kommit fram till att denna nedreglering är helt beroende av CTLA-4, en receptor som konstitutivt uttrycks av de regulatoriska T cellerna. Nedregleringen är helt oberoende av selektiv celldöd bland dendritiska celler med högt uttryck av CD80 och CD86. Regulatoriska T celler är vidare involverade i transplantations tolerans. Vi har närmare studerat denna funktion och har visat att transplantations tolerans genom behandling med substanserna, CTLA-4Ig, anti-LFA1 och antiCD40L, som blockerar interaktionen mellan T celler och dendritiska celler kan genereras även i frånvaro av regulatoriska T celler. De regulatoriska T cellerna verkar snarare vara involverade i ett senare skede av acceptancen eftersom de förekommer i hög frekvens i accepterade transplantat. Slutligen har toleransmekanismer vid upprepad bakterie exponering studerats. Detta experimentella system kan liknas vid den latens som uppstar vid kronisk infektion. Beroende på om regulatoriska T celler är närvarnde eller inte vid exponeringen så kommer olika typer av tolerans mekanismer att dominera. I fallet då regulatoriska T celler är närvarnde under bakterie exponeringen har vi visat att de ökar i frekvens, troligen pga selektiv död bland övriga bakterie specifika T celler. Detta kunde fastställas genom detektionen av Foxp3 uttryckande celler. Foxp3 uttrycks nämligen specifikt av de naturligt förekommande regulatoriska T cellerna. I frånvaro av naturligt förekommande regulatoriska T celler genereras en annan typ av T celler som också de har förmågan att förhindra den bakterie specifika T cells reaktiviteten. Att dessa celler var av en annan typ kunde fastställas genom att de saknade uttryck av Foxp3. (Less)
Abstract
This thesis is based on three original papers with the overall aim to study the mechanisms of induction and function of Foxp3+CD4+CD25+ regulatory T cells.



Regulatory T cells induce down-modulation of costimulatory molecules CD80 and CD86 on dendritic cells in vitro. In the first study we further show that the extent of down-modulation is functionally significant since regulatory T cell conditioned DCs induce poor T cell proliferation responses. We further show that down-modulation is induced rapidly and is dependent on CTLA-4, expressed by the regulatory T cells. Regulatory T cells have been reported to kill antigen-presenting cells. Yet we demonstrate here that down-modulation is not a result of selective killing of... (More)
This thesis is based on three original papers with the overall aim to study the mechanisms of induction and function of Foxp3+CD4+CD25+ regulatory T cells.



Regulatory T cells induce down-modulation of costimulatory molecules CD80 and CD86 on dendritic cells in vitro. In the first study we further show that the extent of down-modulation is functionally significant since regulatory T cell conditioned DCs induce poor T cell proliferation responses. We further show that down-modulation is induced rapidly and is dependent on CTLA-4, expressed by the regulatory T cells. Regulatory T cells have been reported to kill antigen-presenting cells. Yet we demonstrate here that down-modulation is not a result of selective killing of DCs expressing high level of costimulatory molecules. We propose that regulatory T cells down-modulate B7-molecules on DCs in a CTLA-4-dependent way, thereby enhancing suppression of T cell activity.



Previous studies have demonstrated that anti-CD40L or anti-B7 require the presence of CD4+CD25+ regulatory T cells for induction of antigen specific hypo-responsiveness. Other tolerance strategies involving regulatory T cells have shown a dependency on IL-10. The objective of the second study was to investigate the role of Foxp3+regulatory T cells and IL-10 in the induction of transplant tolerance by treatment with CTLA4Ig, anti-CD40L and anti-LFA-1. We demonstrate here that neither T cell derived IL-10 nor the presence of regulatory T cells is essential for induction of graft acceptance in mice treated with costimulation blockade. However, CD4+ T cells depleted of regulatory cells convert into CD4+CD25+ T cells in the periphery of treated mice and histological analysis revealed accumulation of a high number of CD4+Foxp3+ T cells specifically in long term accepted grafts. Suggesting that CD4+Foxp3+ T cells may be involved in the long-term acceptance of allografts induced by costimulation blockade.



Repeated immunization of mice with staphylococcal enterotoxin B (SEB) induces extensive deletion of target CD4+ T cells. Some target cells are however spared and become anergic. In the third study we report that the T cell anergy correlates with an increased proportion of Foxp3+ cells among target T cells, mainly caused by a reduced number of Foxp3- cells. The anergic CD4+ target T cells from rag-2 deficient TCR-transgenic mice was previously shown to contain regulatory T cells with distinct suppressor cell function. We show here that these anergic cells lack Foxp3-expression, but that cells from the rag-2 deficient animals can be induced to express this factor when appropriately stimulated in vivo or in vitro. These data indicate that the distinct suppressor cell function of the anergic CD4+ T cells from rag-2 deficient and rag-2 sufficient mice is due to differential Foxp3 expression by these cells. Further, the absence of Foxp3 expressing cells in naive rag-2 deficient TCR transgenic mice reveals the induction of functionally distinct regulatory cells by repeated SEB immunization. (Less)
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author
supervisor
opponent
  • Associate Professor Lafaille, Juan, Skirball Institute of Biomolecular Science
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Immunologi, serologi, transplantation, regulatory T cell, serology, Immunology, superantigen, costimulation, dendritic cell, Foxp3
pages
54 pages
publisher
Department of Experimental Medical Science, Lund Univeristy
defense location
GK lecture hall, BMC, Lund University
defense date
2006-05-29 10:00
ISSN
1652-8220
ISBN
91-85481-89-0
language
English
LU publication?
yes
id
0c1a8bf4-9aa2-436c-b52a-6811caa7d513 (old id 546884)
date added to LUP
2007-09-17 10:54:13
date last changed
2018-11-21 20:46:08
@phdthesis{0c1a8bf4-9aa2-436c-b52a-6811caa7d513,
  abstract     = {This thesis is based on three original papers with the overall aim to study the mechanisms of induction and function of Foxp3+CD4+CD25+ regulatory T cells.<br/><br>
<br/><br>
Regulatory T cells induce down-modulation of costimulatory molecules CD80 and CD86 on dendritic cells in vitro. In the first study we further show that the extent of down-modulation is functionally significant since regulatory T cell conditioned DCs induce poor T cell proliferation responses. We further show that down-modulation is induced rapidly and is dependent on CTLA-4, expressed by the regulatory T cells. Regulatory T cells have been reported to kill antigen-presenting cells. Yet we demonstrate here that down-modulation is not a result of selective killing of DCs expressing high level of costimulatory molecules. We propose that regulatory T cells down-modulate B7-molecules on DCs in a CTLA-4-dependent way, thereby enhancing suppression of T cell activity.<br/><br>
<br/><br>
Previous studies have demonstrated that anti-CD40L or anti-B7 require the presence of CD4+CD25+ regulatory T cells for induction of antigen specific hypo-responsiveness. Other tolerance strategies involving regulatory T cells have shown a dependency on IL-10. The objective of the second study was to investigate the role of Foxp3+regulatory T cells and IL-10 in the induction of transplant tolerance by treatment with CTLA4Ig, anti-CD40L and anti-LFA-1. We demonstrate here that neither T cell derived IL-10 nor the presence of regulatory T cells is essential for induction of graft acceptance in mice treated with costimulation blockade. However, CD4+ T cells depleted of regulatory cells convert into CD4+CD25+ T cells in the periphery of treated mice and histological analysis revealed accumulation of a high number of CD4+Foxp3+ T cells specifically in long term accepted grafts. Suggesting that CD4+Foxp3+ T cells may be involved in the long-term acceptance of allografts induced by costimulation blockade.<br/><br>
<br/><br>
Repeated immunization of mice with staphylococcal enterotoxin B (SEB) induces extensive deletion of target CD4+ T cells. Some target cells are however spared and become anergic. In the third study we report that the T cell anergy correlates with an increased proportion of Foxp3+ cells among target T cells, mainly caused by a reduced number of Foxp3- cells. The anergic CD4+ target T cells from rag-2 deficient TCR-transgenic mice was previously shown to contain regulatory T cells with distinct suppressor cell function. We show here that these anergic cells lack Foxp3-expression, but that cells from the rag-2 deficient animals can be induced to express this factor when appropriately stimulated in vivo or in vitro. These data indicate that the distinct suppressor cell function of the anergic CD4+ T cells from rag-2 deficient and rag-2 sufficient mice is due to differential Foxp3 expression by these cells. Further, the absence of Foxp3 expressing cells in naive rag-2 deficient TCR transgenic mice reveals the induction of functionally distinct regulatory cells by repeated SEB immunization.},
  author       = {Oderup, Cecilia},
  isbn         = {91-85481-89-0},
  issn         = {1652-8220},
  keyword      = {Immunologi,serologi,transplantation,regulatory T cell,serology,Immunology,superantigen,costimulation,dendritic cell,Foxp3},
  language     = {eng},
  pages        = {54},
  publisher    = {Department of Experimental Medical Science, Lund Univeristy},
  school       = {Lund University},
  title        = {On the induction and function of Foxp3+ regulatory T cells},
  year         = {2006},
}