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Regulation of the immunological synapse by the phosphatase PTPN22

Hedbys, Johan (2017) MOBN01 20162
Degree Projects in Molecular Biology
Abstract
Integrins are adhesion molecules that control cell to cell interactions and play a fundamental role in adhesion of T cells during an immune response. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is an important regulatory factor of the integrin lymphocyte function-associated antigen 1 (LFA1). A single-nucleotide polymorphism in the gene coding for PTPN22 has previously been linked as a risk factor for autoimmune diseases like type 1 diabetes. Here we study PTPN22 in relation to adhesion strength of T cells during the formation of the immunological synapse. We have seen that cells lacking PTPN22 through knock down adheres significantly stronger to Muromonab-CD3 (OKT3) with both the ligand to LFA1, intercellular adhesion... (More)
Integrins are adhesion molecules that control cell to cell interactions and play a fundamental role in adhesion of T cells during an immune response. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is an important regulatory factor of the integrin lymphocyte function-associated antigen 1 (LFA1). A single-nucleotide polymorphism in the gene coding for PTPN22 has previously been linked as a risk factor for autoimmune diseases like type 1 diabetes. Here we study PTPN22 in relation to adhesion strength of T cells during the formation of the immunological synapse. We have seen that cells lacking PTPN22 through knock down adheres significantly stronger to Muromonab-CD3 (OKT3) with both the ligand to LFA1, intercellular adhesion molecule 1 (ICAM1), present and absent. This has further increased as well as supported previous knowledge by indicating that PTPN22 is a negative regulator of LFA1 as well as the T cell receptor. Furthermore we have also used confocal microscopy to see how PTPN22 appears to co-localize with its substrates lck, vav and zap70 in T cells forming synapses with and without ICAM1 present. (Less)
Popular Abstract
Mutation in immune cells causes autoimmune diseases

Humans have an immune system that constantly surveillance our body in the pursuit of foreign organisms. If the immune system works the way it is meant to, it finds and destroys substances that have found their way into our body, like pathogens. These substances are generally viruses or bacteria. But if the immune system is faulty it might find and attack our own cells. This is the case with autoimmune diseases like type 1 diabetes.

The immune system consists of many different cells. The T cells are responsible for the surveillance of our bodies but they need the help of different cells generally termed antigen presenting cells. When an antigen presenting cell finds a substrate that... (More)
Mutation in immune cells causes autoimmune diseases

Humans have an immune system that constantly surveillance our body in the pursuit of foreign organisms. If the immune system works the way it is meant to, it finds and destroys substances that have found their way into our body, like pathogens. These substances are generally viruses or bacteria. But if the immune system is faulty it might find and attack our own cells. This is the case with autoimmune diseases like type 1 diabetes.

The immune system consists of many different cells. The T cells are responsible for the surveillance of our bodies but they need the help of different cells generally termed antigen presenting cells. When an antigen presenting cell finds a substrate that seems foreign, it takes it to the T cells. The antigen presenting cells express something called MHC which the T cell binds to and is then able to see what the antigen presenting cell has found. The T cell then judges whether to illicit an immune response or not towards the substrate presented. The binding of the T cell to the antigen presenting cell is to great extent regulated by adhesion molecules called integrins, which sits upon the T cell. These adhesion molecules work like anchors and firmly connects the cells in something called an immunological synapse. If the integrins work too well and the connection between the cells become too strong, the risk of the T cell misjudging the proteins shown by the antigen presenting cell increases. If this is the case the T cell might elicits an immune response towards a protein that is in fact part of our own body and an autoimmune disease takes form.

PTPN22
Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) is a protein that has been seen to affect the T cells responsiveness in regulatory ways. Around ten percent of the people in Sweden have something called a single nucleotide polymorphism which means that a very small change has occurred in the gene coding for PTPN22. This small change has damaged the protein and this small damage is now being researched because it seems it increases the risk of autoimmune diseases.
Here we have observed the effect of PTPN22 and how it affects the integrins, the anchors of the T cells. We allowed T cells to form immunological synapses with the ligand to the integrin present or not (without the ligands the integrins have nothing to put their anchors in). By using a microscopy technique called interference reflection microscopy, we could measure how strongly the T cells adhered during the forming of the immunological synapse. The immunological synapse was seen to be bound stronger if it was formed with the ligands to integrins present. By doing this with cells where we had knocked downed, i.e. removed, PTPN22 and compare it to cells with PTPN22 present we saw that the cells without PTPN22 bound much stronger during the formation of the immunological synapse. These results show how PTPN22 has an inhibitory effect upon the integrins during the forming of the immunological synapse. This could indicate that the ten percent of the population with damaged PTPN22 also might have their integrins adhere stronger to the antigen presenting cells and by this mechanism increase the risk of autoimmune diseases.

Master’s Degree Project in Molecular Biology – Medical Biology 45 credits 2017.
Department of Biology, Lund University.
Advisor: Lena M Svensson, Medical faculty/ Institution for experimental medical science/ Leukocyte migration. (Less)
Please use this url to cite or link to this publication:
author
Hedbys, Johan
supervisor
organization
course
MOBN01 20162
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
8925325
date added to LUP
2017-09-11 15:52:45
date last changed
2017-09-11 15:52:45
@misc{8925325,
  abstract     = {Integrins are adhesion molecules that control cell to cell interactions and play a fundamental role in adhesion of T cells during an immune response. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is an important regulatory factor of the integrin lymphocyte function-associated antigen 1 (LFA1). A single-nucleotide polymorphism in the gene coding for PTPN22 has previously been linked as a risk factor for autoimmune diseases like type 1 diabetes. Here we study PTPN22 in relation to adhesion strength of T cells during the formation of the immunological synapse. We have seen that cells lacking PTPN22 through knock down adheres significantly stronger to Muromonab-CD3 (OKT3) with both the ligand to LFA1, intercellular adhesion molecule 1 (ICAM1), present and absent. This has further increased as well as supported previous knowledge by indicating that PTPN22 is a negative regulator of LFA1 as well as the T cell receptor. Furthermore we have also used confocal microscopy to see how PTPN22 appears to co-localize with its substrates lck, vav and zap70 in T cells forming synapses with and without ICAM1 present.},
  author       = {Hedbys, Johan},
  language     = {eng},
  note         = {Student Paper},
  title        = {Regulation of the immunological synapse by the phosphatase PTPN22},
  year         = {2017},
}