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Characterization of CD8+ T cell subtypes induced by 4-1BB costimulation in mice

Dahl, Martin (2012) MOBT13 20112
Degree Projects in Molecular Biology
Abstract
Abstract

4-1BB (CD137/TNFRSF9) is a costimulatory receptor expressed by several cellular subsets of the immune system, but is commonly associated with CD8+ T cells. Stimulation of 4-1BB on CD8+ T cells with agonistic antibodies (α-4-1BB) causes a potent proliferation signal and an upregulated expression of CD11c. CD11c+CD8+ have previously been recognized to suppress other immune cells, such as FoxP3+CD4+ regulatory T cells, leading to for example an increased level of tumor rejection. Antibody-mediated stimulation of 4-1BB also causes germinal center (GC) B cells and follicular dendritic cells (FDCs), localized in the B cell follicles, to disappear. By studying spleens and mesenteric lymph nodes (MLNs) from immunized mice treated with... (More)
Abstract

4-1BB (CD137/TNFRSF9) is a costimulatory receptor expressed by several cellular subsets of the immune system, but is commonly associated with CD8+ T cells. Stimulation of 4-1BB on CD8+ T cells with agonistic antibodies (α-4-1BB) causes a potent proliferation signal and an upregulated expression of CD11c. CD11c+CD8+ have previously been recognized to suppress other immune cells, such as FoxP3+CD4+ regulatory T cells, leading to for example an increased level of tumor rejection. Antibody-mediated stimulation of 4-1BB also causes germinal center (GC) B cells and follicular dendritic cells (FDCs), localized in the B cell follicles, to disappear. By studying spleens and mesenteric lymph nodes (MLNs) from immunized mice treated with α-4-1BB we show that two phenotypically distinct CD8+ T cell subtypes emerge. Thus except from the previously recognised CD11c+ subset, we also identify a subset distinguished by the expression of the chemokine receptor CXCR5, of which some also express CD11c. Although these events are accompanied by a complete elimination of antigen-specific CD4+ T cells and GC, the expansion of CD11c+, or CXCR5+, CD8+ T cells does not require the antigen or adjuvant used for immunization. Neither is the expansion of these CD8+ T cells augmented as a consequence of increased precursor frequency of antigen-specific CD4+ T cells, indicating that they are not directly reactive to these subsets. However, α-4-1BB treatment fails to stimulate the generation of CD11c+ and CXCR5+ CD8+ T cells in the absence of TCR signalling. Collectively these results indicate that the expansion of these atypical CD8+ T cells in response to α-4-1BB treatment is driven by self-antigens, which are thus not necessarily displayed by concurrently activated antigen-specific CD4+ T cells. To what extent these atypical CD8+ T cell subsets underlie the α-4-1BB mediated elimination of antigen- specific CD4+ T cells, FDCs and GCs, and what role the observed accumulation of DCs within the B cell follicles plays in this process, remains to be determined. (Less)
Abstract (Swedish)
Aktivering av immunförsvaret dämpar den samme

Kroppens immunförsvar består av en mängd olika typer av specialiserade celler, alla med sina unika egenskaper och nischer. För att immunförsvaret ska fungera så optimalt som möjligt krävs det att cellerna kan interagera och kommunisera med varandra, vilket görs med hjälp av proteiner som finns på cellernas yta. En typ av celler, som kallas CD8+ T celler (för att de har ytproteinet CD8), har förmågan att läsa av vilka slags proteiner som finns inuti andra celler genom att interagera med ett av deras ytprotein (MHC-I). Om cellerna visar en massa proteiner som tillhör bakterier, virus eller som, p.g.a. skador, är förvanskade så kommer den CD8+ T cellen att ge den infekterade eller skadade... (More)
Aktivering av immunförsvaret dämpar den samme

Kroppens immunförsvar består av en mängd olika typer av specialiserade celler, alla med sina unika egenskaper och nischer. För att immunförsvaret ska fungera så optimalt som möjligt krävs det att cellerna kan interagera och kommunisera med varandra, vilket görs med hjälp av proteiner som finns på cellernas yta. En typ av celler, som kallas CD8+ T celler (för att de har ytproteinet CD8), har förmågan att läsa av vilka slags proteiner som finns inuti andra celler genom att interagera med ett av deras ytprotein (MHC-I). Om cellerna visar en massa proteiner som tillhör bakterier, virus eller som, p.g.a. skador, är förvanskade så kommer den CD8+ T cellen att ge den infekterade eller skadade cellen en signal om att ta död på sig själv. Detta kallas ofta för programerad celldöd och är en viktig process för att hålla individen frisk från infektioner.

För att CD8+ T celler ska aktiveras krävs det att de först interagerar med en annan typ av celler, s.kl. dendritiska celler, som talar om för CD8+ T cellerna att det finns virus-, bakterie- eller skadade proteiner hos celler i omgivningen. Ett av de signalproteiner hos CD8+ T celler som dendrit cellerna binder till och kommunicerar via kallas 4-1BB. Det är dessa interaktioner, samt vad en överstimulering av CD8+ T celler orsakar i möss som jag har undersökt närmare i mitt projekt.

Det man främst ser i vävnader hos de behandlade mössen är att specifika typer av celler, ex. antikroppsbildande celler, minskar kraftigt p.g.a. de överaktiva CD8+ T cellernas närvaro, se Figur. Den här typen av behandling har man också börjat experimentera med om den skulle kunna vara effektiv för att bota olika typer av tumörer och leukemier.


Handledare Bengt Johansson-Lindbom
Examensarbete för masterexamen i molekylärbiologi: immunologi 60 hp, 2012
Biologiska institutionen, Lunds universitet (Less)
Please use this url to cite or link to this publication:
author
Dahl, Martin
supervisor
organization
course
MOBT13 20112
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
3633200
date added to LUP
2013-04-12 14:16:40
date last changed
2013-04-12 14:16:40
@misc{3633200,
  abstract     = {Abstract

4-1BB (CD137/TNFRSF9) is a costimulatory receptor expressed by several cellular subsets of the immune system, but is commonly associated with CD8+ T cells. Stimulation of 4-1BB on CD8+ T cells with agonistic antibodies (α-4-1BB) causes a potent proliferation signal and an upregulated expression of CD11c. CD11c+CD8+ have previously been recognized to suppress other immune cells, such as FoxP3+CD4+ regulatory T cells, leading to for example an increased level of tumor rejection. Antibody-mediated stimulation of 4-1BB also causes germinal center (GC) B cells and follicular dendritic cells (FDCs), localized in the B cell follicles, to disappear. By studying spleens and mesenteric lymph nodes (MLNs) from immunized mice treated with α-4-1BB we show that two phenotypically distinct CD8+ T cell subtypes emerge. Thus except from the previously recognised CD11c+ subset, we also identify a subset distinguished by the expression of the chemokine receptor CXCR5, of which some also express CD11c. Although these events are accompanied by a complete elimination of antigen-specific CD4+ T cells and GC, the expansion of CD11c+, or CXCR5+, CD8+ T cells does not require the antigen or adjuvant used for immunization. Neither is the expansion of these CD8+ T cells augmented as a consequence of increased precursor frequency of antigen-specific CD4+ T cells, indicating that they are not directly reactive to these subsets. However, α-4-1BB treatment fails to stimulate the generation of CD11c+ and CXCR5+ CD8+ T cells in the absence of TCR signalling. Collectively these results indicate that the expansion of these atypical CD8+ T cells in response to α-4-1BB treatment is driven by self-antigens, which are thus not necessarily displayed by concurrently activated antigen-specific CD4+ T cells. To what extent these atypical CD8+ T cell subsets underlie the α-4-1BB mediated elimination of antigen- specific CD4+ T cells, FDCs and GCs, and what role the observed accumulation of DCs within the B cell follicles plays in this process, remains to be determined.},
  author       = {Dahl, Martin},
  language     = {eng},
  note         = {Student Paper},
  title        = {Characterization of CD8+ T cell subtypes induced by 4-1BB costimulation in mice},
  year         = {2012},
}