Compensatory Mechanisms Allow Undersized Anchor-Deficient Class i MHC Ligands to Mediate Pathogenic Autoreactive T Cell Responses

Deanna Lamont, Gayatri Mukherjee, P. Rajesh Kumar, Dibyendu Samanta, Caroline G. McPhee, Thomas W H Kay, Steven C. Almo, Teresa P. DiLorenzo, David V. Serreze

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Self-reactive T cells must escape thymic negative selection to mediate pathogenic autoimmunity. In the NOD mouse model of autoimmune diabetes, several β cell-cytotoxic CD8 T cell populations are known, with the most aggressive of these represented by AI4, a T cell clone with promiscuous Ag-recognition characteristics. We identified a long-elusive β cell-specific ligand for AI4 as an unusually short H-2Db-binding 7-mer peptide lacking a C-terminal anchor residue and derived from the insulin A chain (InsA14-20). Crystallography reveals that compensatory mechanisms permit peptides lacking a C-terminal anchor to bind sufficiently to the MHC to enable destructive T cell responses, yet allow cognate T cells to avoid negative selection. InsA14-20shares two solvent-exposed residues with previously identified AI4 ligands, providing a structural explanation for AI4's promiscuity. Detection of AI4-like T cells, using mimotopes of InsA14-20with improved H-2Db-binding characteristics, establishes the AI4-like T cell population as a consistent feature of the islet infiltrates of NOD mice. Our work establishes undersized peptides as previously unrecognized targets of autoreactive CD8 T cells and presents a strategy for their further exploration as Ags in autoimmune disease. Copyright

Original languageEnglish (US)
Pages (from-to)2135-2146
Number of pages12
JournalJournal of Immunology
Volume193
Issue number5
DOIs
StatePublished - Sep 1 2014

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Ligands
T-Lymphocytes
Inbred NOD Mouse
Peptides
Crystallography
Autoimmunity
Type 1 Diabetes Mellitus
Population
Autoimmune Diseases
Clone Cells
Insulin

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Lamont, D., Mukherjee, G., Kumar, P. R., Samanta, D., McPhee, C. G., Kay, T. W. H., ... Serreze, D. V. (2014). Compensatory Mechanisms Allow Undersized Anchor-Deficient Class i MHC Ligands to Mediate Pathogenic Autoreactive T Cell Responses. Journal of Immunology, 193(5), 2135-2146. https://doi.org/10.4049/jimmunol.1400997

Compensatory Mechanisms Allow Undersized Anchor-Deficient Class i MHC Ligands to Mediate Pathogenic Autoreactive T Cell Responses. / Lamont, Deanna; Mukherjee, Gayatri; Kumar, P. Rajesh; Samanta, Dibyendu; McPhee, Caroline G.; Kay, Thomas W H; Almo, Steven C.; DiLorenzo, Teresa P.; Serreze, David V.

In: Journal of Immunology, Vol. 193, No. 5, 01.09.2014, p. 2135-2146.

Research output: Contribution to journalArticle

Lamont, Deanna ; Mukherjee, Gayatri ; Kumar, P. Rajesh ; Samanta, Dibyendu ; McPhee, Caroline G. ; Kay, Thomas W H ; Almo, Steven C. ; DiLorenzo, Teresa P. ; Serreze, David V. / Compensatory Mechanisms Allow Undersized Anchor-Deficient Class i MHC Ligands to Mediate Pathogenic Autoreactive T Cell Responses. In: Journal of Immunology. 2014 ; Vol. 193, No. 5. pp. 2135-2146.
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