CD8 T cell autoreactivity to preproinsulin epitopes with very low human leucocyte antigen class I binding affinity

被引:37
|
作者
Abreu, J. R. F. [1 ]
Martina, S. [1 ]
Stuart, A. A. Verrijn [1 ,2 ,3 ]
Fillie, Y. E. [1 ]
Franken, K. L. M. C. [1 ]
Drijfhout, J. W. [1 ]
Roep, B. O. [1 ,4 ]
机构
[1] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands
[2] UMC Utrecht, Dept Pediat Endocrinol, Utrecht, Netherlands
[3] UMC Utrecht, Ctr Cellular & Mol Intervent, Utrecht, Netherlands
[4] JDRF Ctr Beta Cell Therapy Diabet Europe, Leiden, Netherlands
关键词
affinity; autoimmunity; CD8 T cell; tolerance; type; 1; diabetes; LOW-AVIDITY RECOGNITION; CENTRAL TOLERANCE; MICE RECOGNIZE; MHC MULTIMERS; INSULIN GENE; HUMAN THYMUS; PEPTIDE; EXPRESSION; MOLECULES; SELECTION;
D O I
10.1111/j.1365-2249.2012.04635.x
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Beta cells presenting islet epitopes are recognized and destroyed by autoreactive CD8 T cells in type 1 diabetes. These islet-specific T cells are believed to react with epitopes binding with high affinity to human leucocyte antigen (HLA) expressed on beta cells. However, this assumption might be flawed in case of islet autoimmunity. We evaluated T cell recognition of the complete array of preproinsulin (PPI) peptides with regard to HLA binding affinity and T cell recognition. In a comprehensive approach, 203 overlapping 910mer PPI peptides were tested for HLA-A2 binding and subjected to binding algorithms. Subsequently, a high-throughput assay was employed to detect PPI-specific T cells in patient blood, in which conditional HLA ligands were destabilized by ultraviolet irradiation and HLA molecules refolded with arrays of PPI peptides, followed by quantum-dot labelling and T cell staining. Analysis of patient blood revealed high frequencies of CD8 T cells recognizing very low HLA binding peptides. Of 28 peptides binding to HLA-A2, a majority was predicted not to bind. Unpredicted peptides bound mainly with low affinities. HLA binding affinity and immunogenicity may not correlate in autoimmunity. Algorithms used to predict high-affinity HLA peptide binders discount the majority of low-affinity HLA binding epitopes. Appreciation that peptides binding HLA with very low affinity can act as targets of autoreactive T cells may help to understand loss of tolerance and disease pathogenesis and possibly point to tissue-specific immune intervention targets.
引用
收藏
页码:57 / 65
页数:9
相关论文
共 50 条
  • [31] Low CD4/CD8 T-Cell Ratio Associated with Inflammatory Arthropathy in Human T-Cell Leukemia Virus Type I Tax Transgenic Mice
    Ohsugi, Takeo
    Kumasaka, Toshio
    PLOS ONE, 2011, 6 (04):
  • [32] Transcriptional Control of Cell Fate Determination in Antigen-Experienced CD8 T Cells
    Tsuda, Shanel
    Pipkin, Matthew E.
    COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2022, 14 (02):
  • [33] Identification of overlapping epitopes in mutant ras oncogene peptides that activate CD4(+) and CD8(+)T cell responses
    Abrams, SI
    Stanziale, SF
    Lunin, SD
    Zaremba, S
    Schlom, J
    EUROPEAN JOURNAL OF IMMUNOLOGY, 1996, 26 (02) : 435 - 443
  • [34] Tumour-associated glycan modifications of antigen enhance MGL2 dependent uptake and MHC class I restricted CD8 T cell responses
    Singh, Satwinder Kaur
    Streng-Ouwehand, Ingeborg
    Litjens, Manja
    Kalay, Hakan
    Saeland, Eirikur
    van Kooyk, Yvette
    INTERNATIONAL JOURNAL OF CANCER, 2011, 128 (06) : 1371 - 1383
  • [35] Cutting Edge: Inhibitory Effects of CD4 and CD8 on T Cell Activation Induced by High-Affinity Noncognate Ligands
    Chervin, Adam S.
    Stone, Jennifer D.
    Bowerman, Natalie A.
    Kranz, David M.
    JOURNAL OF IMMUNOLOGY, 2009, 183 (12) : 7639 - 7643
  • [36] Cytotoxic CD8α+ leucocytes have heterogeneous features in antigen recognition and class I MHC restriction in grouper
    Chang, Yun-Tsan
    Kai, Yu-Hsuan
    Chi, Shau-Chi
    Song, Yen-Ling
    FISH & SHELLFISH IMMUNOLOGY, 2011, 30 (06) : 1283 - 1293
  • [37] Viral and tumor antigen-specific CD8 T-cell responses in Merkel cell carcinoma
    Samimi, Mahtab
    Benlalam, Houssem
    Aumond, Pascal
    Gaboriaud, Pauline
    Fradin, Delphine
    Kervarrec, Thibault
    Florenceau, Laetitia
    Vignard, Virginie
    Blom, Astrid
    Touze, Antoine
    Gervois, Nadine
    Labarriere, Nathalie
    CELLULAR IMMUNOLOGY, 2019, 344
  • [38] FACS isolation of low percentage human antigen-specific CD8+ T cells based on activation-induced CD3 and CD8 downregulation
    Huang, Miaojuan
    Zhang, Jian
    Chen, Weisan
    JOURNAL OF IMMUNOLOGICAL METHODS, 2019, 472 : 35 - 43
  • [39] Deep learning enhances the prediction of HLA class I-presented CD8+ T cell epitopes in foreign pathogens
    Wohlwend, Jeremy
    Nathan, Anusha
    Shalon, Nitan
    Crain, Charles R.
    Tano-Menka, Rhoda
    Goldberg, Benjamin
    Richards, Emma
    Gaiha, Gaurav D.
    Barzilay, Regina
    NATURE MACHINE INTELLIGENCE, 2025, 7 (02) : 232 - 243
  • [40] Allospecific Rejection of MHC Class I-Deficient Bone Marrow by CD8 T Cells
    Haspot, F.
    Li, H. W.
    Lucas, C. L.
    Fehr, T.
    Beyaz, S.
    Sykes, M.
    AMERICAN JOURNAL OF TRANSPLANTATION, 2014, 14 (01) : 49 - 58