scholarly journals Faculty Opinions recommendation of Cutting edge: type 1 diabetes occurs despite robust anergy among endogenous insulin-specific CD4 T cells in NOD mice.

Author(s):  
David Serreze
2013 ◽  
Vol 191 (10) ◽  
pp. 4913-4917 ◽  
Author(s):  
Kristen E. Pauken ◽  
Jonathan L. Linehan ◽  
Justin A. Spanier ◽  
Nathanael L. Sahli ◽  
Lokesh A. Kalekar ◽  
...  

Cytokine ◽  
2012 ◽  
Vol 59 (3) ◽  
pp. 542-543
Author(s):  
P. Biswas ◽  
S. Gupta ◽  
E. Chang ◽  
G. Bhagat ◽  
A. Pernis

2021 ◽  
Vol 12 ◽  
Author(s):  
Laurie G. Landry ◽  
Amanda M. Anderson ◽  
Holger A. Russ ◽  
Liping Yu ◽  
Sally C. Kent ◽  
...  

Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.


2006 ◽  
Vol 119 ◽  
pp. S166
Author(s):  
Tihamer Orban ◽  
Janos Kis ◽  
Peter Engelmann ◽  
Laszlo Szereday ◽  
Geoffrey Richman ◽  
...  

2019 ◽  
Vol 4 (38) ◽  
pp. eaaw6329 ◽  
Author(s):  
Louis Gioia ◽  
Marie Holt ◽  
Anne Costanzo ◽  
Siddhartha Sharma ◽  
Brian Abe ◽  
...  

The class II region of the major histocompatibility complex (MHC) locus is the main contributor to the genetic susceptibility to type 1 diabetes (T1D). The loss of an aspartic acid at position 57 of diabetogenic HLA-DQβ chains supports this association; this single amino acid change influences how TCRs recognize peptides in the context of HLA-DQ8 and I-Ag7 using a mechanism termed the P9 switch. Here, we built register-specific insulin peptide MHC tetramers to examine CD4+ T cell responses to Ins12–20 and Ins13–21 peptides during the early prediabetic phase of disease in nonobese diabetic (NOD) mice. A single-cell analysis of anti-insulin CD4+ T cells performed in 6- and 12-week-old NOD mice revealed tissue-specific gene expression signatures. TCR signaling and clonal expansion were found only in the islets of Langerhans and produced either classical TH1 differentiation or an unusual Treg phenotype, independent of TCR usage. The early phase of the anti-insulin response was dominated by T cells specific for Ins12–20, the register that supports a P9 switch mode of recognition. The presence of the P9 switch was demonstrated by TCR sequencing, reexpression, mutagenesis, and functional testing of TCRαβ pairs in vitro. Genetic correction of the I-Aβ57 mutation in NOD mice resulted in the disappearance of D/E residues in the CDR3β of anti-Ins12–20 T cells. These results provide a mechanistic molecular explanation that links the characteristic MHC class II polymorphism of T1D with the recognition of islet autoantigens and disease onset.


Diabetes ◽  
2020 ◽  
Vol 69 (4) ◽  
pp. 661-669 ◽  
Author(s):  
Jan Knoop ◽  
Anne Eugster ◽  
Anita Gavrisan ◽  
Ramona Lickert ◽  
Eva-Maria Sedlmeier ◽  
...  
Keyword(s):  
T Cells ◽  

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