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.
机构:
Kumamoto Univ, Div Microbiol & Genet, Ctr Anim Resources & Dev, Inst Resource Dev & Anal, Kumamoto, JapanKumamoto Univ, Div Microbiol & Genet, Ctr Anim Resources & Dev, Inst Resource Dev & Anal, Kumamoto, Japan
Ohsugi, Takeo
Kumasaka, Toshio
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机构:
Japanese Red Cross Med Ctr, Dept Pathol, Tokyo, JapanKumamoto Univ, Div Microbiol & Genet, Ctr Anim Resources & Dev, Inst Resource Dev & Anal, Kumamoto, Japan
机构:
MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
MIT, Jameel Clin, Cambridge, MA 02139 USAMIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
Wohlwend, Jeremy
Nathan, Anusha
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机构:
Ragon Inst Mass Gen MIT & Harvard, Cambridge, MA 02139 USA
Harvard Med Sch, MIT, Program Hlth Sci & Technol, Boston, MA 02115 USAMIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
Nathan, Anusha
Shalon, Nitan
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机构:
MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
MIT, Jameel Clin, Cambridge, MA 02139 USAMIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
Shalon, Nitan
Crain, Charles R.
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机构:
Ragon Inst Mass Gen MIT & Harvard, Cambridge, MA 02139 USAMIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
Crain, Charles R.
Tano-Menka, Rhoda
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Ragon Inst Mass Gen MIT & Harvard, Cambridge, MA 02139 USAMIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
Tano-Menka, Rhoda
Goldberg, Benjamin
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h-index: 0
机构:
Ragon Inst Mass Gen MIT & Harvard, Cambridge, MA 02139 USAMIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
Goldberg, Benjamin
Richards, Emma
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Ragon Inst Mass Gen MIT & Harvard, Cambridge, MA 02139 USAMIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
Richards, Emma
Gaiha, Gaurav D.
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h-index: 0
机构:
Ragon Inst Mass Gen MIT & Harvard, Cambridge, MA 02139 USA
Harvard Med Sch, MIT, Program Hlth Sci & Technol, Boston, MA 02115 USA
Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USAMIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
Gaiha, Gaurav D.
Barzilay, Regina
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h-index: 0
机构:
MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
MIT, Jameel Clin, Cambridge, MA 02139 USAMIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
机构:
Harvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USAHarvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USA
Haspot, F.
Li, H. W.
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机构:
Harvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USA
Columbia Univ, Coll Phys & Surg, Dept Med, Columbia Ctr Translat Immunol, New York, NY USAHarvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USA
Li, H. W.
Lucas, C. L.
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h-index: 0
机构:
Harvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USAHarvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USA
Lucas, C. L.
Fehr, T.
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h-index: 0
机构:
Harvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USAHarvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USA
Fehr, T.
Beyaz, S.
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h-index: 0
机构:
Harvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USAHarvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USA
Beyaz, S.
Sykes, M.
论文数: 0引用数: 0
h-index: 0
机构:
Harvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USA
Columbia Univ, Coll Phys & Surg, Dept Med, Columbia Ctr Translat Immunol, New York, NY USAHarvard Univ, Sch Med, Dept Med, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USA