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MHC class I - Peptide binding and complex stability

Follin, Elna LU (2014) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2014:38.
Abstract
The major histocompatibility class I (MHC-I) genes are highly polymorphic and the proteins that they encode play a crucial role in both the innate and the adaptive immune response. A MHC-I molecule consists of three parts, one polymorphic heavy chain, one invariant light chain, β2-microglobulin and a peptide of usually between 8-11 amino acids in length. The maturation and quality control of MHC-I takes place in the endoplasmic reticulum and involves several different proteins including the MHC-I dedicated protein tapasin.



In this thesis we have studied different parameters important for MHC-I formation and stability in humans and birds. We have used various approaches including in silico prediction methods, biochemical... (More)
The major histocompatibility class I (MHC-I) genes are highly polymorphic and the proteins that they encode play a crucial role in both the innate and the adaptive immune response. A MHC-I molecule consists of three parts, one polymorphic heavy chain, one invariant light chain, β2-microglobulin and a peptide of usually between 8-11 amino acids in length. The maturation and quality control of MHC-I takes place in the endoplasmic reticulum and involves several different proteins including the MHC-I dedicated protein tapasin.



In this thesis we have studied different parameters important for MHC-I formation and stability in humans and birds. We have used various approaches including in silico prediction methods, biochemical assays and cellular assays to elucidate the MHC-I maturation. We show that the functional relationships between MHC-I molecules in passerine birds of different species are based on the MHC-I characteristics such as peptide-binding specificity rather than species characteristics. In addition, passerine MHC-I molecules similar to human MHC-I molecules, have a complex dissociation. This suggests that just as in humans, passerine MHC-I molecules go through different maturation stages that most likely include interaction with quality control proteins such as tapasin.



The cell surface expression of stable MHC-I molecules is crucial for the function of the adaptive immune response and for this reason MHC-I and its related proteins are often a target for viral and tumour evasion strategies. In human cells we show that tapasin promotes the formation of stable cell surface expressed MHC-I molecules and that the dependency on tapasin for a stable cell surface expression varies between different allomorphs (allele specific protein products). The dysregulation of tapasin results in alterations in the peptide repertoire that is presented by MHC-I at the cell surface and most often this induces a decreased stability of the expressed molecules. We here show that by adding certain peptides exogenously to cells deficient in tapasin we were able to increase MHC-I cell surface stability significantly suggesting that exogenous modulations of tapasin deficient cells might be a possible approach in immunotherapy. The formation of aberrant conformations of HLA-B*27:05 has been suggested to play a role in the pathogenesis of ankylosing spondylitis and here we showed that tapasin has a preventive effect on the formation and presentation of aberrant conformations of HLA-B*27:05 at the cell surface.



In conclusion we show that the complex kinetics of MHC-I maturation and stability is a trait shared between birds and humans and we suggest that by studying MHC-I in other species than human we can gain valuable insight into the complex world of MHC-I. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Kaufman, Jim, Department of pathology, University of Cambridge
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2014:38
pages
88 pages
publisher
Department of Experimental Medical Science, Lund Univeristy
defense location
Segerfalksalen, BMC A10, Sölvegatan 19, Lund
defense date
2014-03-28 13:00
ISSN
1652-8220
ISBN
978-91-87651-63-2
language
English
LU publication?
yes
id
5715cf39-827d-436b-93b4-495489201143 (old id 4351751)
date added to LUP
2014-03-07 13:01:45
date last changed
2016-09-19 08:44:48
@phdthesis{5715cf39-827d-436b-93b4-495489201143,
  abstract     = {The major histocompatibility class I (MHC-I) genes are highly polymorphic and the proteins that they encode play a crucial role in both the innate and the adaptive immune response. A MHC-I molecule consists of three parts, one polymorphic heavy chain, one invariant light chain, β2-microglobulin and a peptide of usually between 8-11 amino acids in length. The maturation and quality control of MHC-I takes place in the endoplasmic reticulum and involves several different proteins including the MHC-I dedicated protein tapasin. <br/><br>
<br/><br>
In this thesis we have studied different parameters important for MHC-I formation and stability in humans and birds. We have used various approaches including in silico prediction methods, biochemical assays and cellular assays to elucidate the MHC-I maturation. We show that the functional relationships between MHC-I molecules in passerine birds of different species are based on the MHC-I characteristics such as peptide-binding specificity rather than species characteristics. In addition, passerine MHC-I molecules similar to human MHC-I molecules, have a complex dissociation. This suggests that just as in humans, passerine MHC-I molecules go through different maturation stages that most likely include interaction with quality control proteins such as tapasin. <br/><br>
<br/><br>
The cell surface expression of stable MHC-I molecules is crucial for the function of the adaptive immune response and for this reason MHC-I and its related proteins are often a target for viral and tumour evasion strategies. In human cells we show that tapasin promotes the formation of stable cell surface expressed MHC-I molecules and that the dependency on tapasin for a stable cell surface expression varies between different allomorphs (allele specific protein products). The dysregulation of tapasin results in alterations in the peptide repertoire that is presented by MHC-I at the cell surface and most often this induces a decreased stability of the expressed molecules. We here show that by adding certain peptides exogenously to cells deficient in tapasin we were able to increase MHC-I cell surface stability significantly suggesting that exogenous modulations of tapasin deficient cells might be a possible approach in immunotherapy. The formation of aberrant conformations of HLA-B*27:05 has been suggested to play a role in the pathogenesis of ankylosing spondylitis and here we showed that tapasin has a preventive effect on the formation and presentation of aberrant conformations of HLA-B*27:05 at the cell surface. <br/><br>
<br/><br>
In conclusion we show that the complex kinetics of MHC-I maturation and stability is a trait shared between birds and humans and we suggest that by studying MHC-I in other species than human we can gain valuable insight into the complex world of MHC-I.},
  author       = {Follin, Elna},
  isbn         = {978-91-87651-63-2},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {88},
  publisher    = {Department of Experimental Medical Science, Lund Univeristy},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {MHC class I - Peptide binding and complex stability},
  volume       = {2014:38},
  year         = {2014},
}