Tolerance to insulin is maintained by Foxp3+ Tregs

A new study in Journal of Immunology suggests that tolerance to insulin is maintained by Foxp3+ Tregs rather than by deletion of insulin-reactive T cell clones. 

 

Here, the authors reconstituted mice with T cells on scid background transduced either with high (4-8) or low (12-4.1) affinity TCR specific for native insulin peptide (insulin epitope B:9–23). In addition, each of TCR construct were fused with either native insulin (INS) or modified insulin carrying super-affinity peptide (R22E). All mice expressing either INS or R22E but not irrelevant HEL were protected from developing diabetes.

The authors showed that while R22E deleted developing insulin-specific T cell clones in the thymus, native INS did not.

In fact, the authors showed that if the T cells also lacked Foxp3 molecule (scid-scurfy), then protection against diabetes was lost in mice exposed to native INS.

This study could be interpreted to show that with the exception of  epitopes which are able to delete (purge) cognate T cell clones in the thymus, tolerance to self in the periphery is maintained by thymic-derived Foxp3+ Tregs.

posted by David Usharauli 





    

Absence of NOD2 signaling protects against chemical[STZ]-induced diabetes

Experimental models developed in "clean" laboratory mice rarely translates to human diseases. For example, NOD mice spontaneously develop Type 1 diabetes, as susceptible humans do, however pancreatic tissue pathology does not match. 

There is another model of T1D in mice called treptozotocin (STZ)-induced diabetes. STZ is toxic to insulin producing β cells in pancreas and drive T1D in a T cell-dependent manner. In new study published in Journal of Experimental Medicine the authors showed that treptozotocin induced T1D depended on gut flora derived muramyl dipeptide → NOD2 signaling.

The authors found that NOD2^-/- mice, but not NOD1^-/- or Rip2^-/- mice, were resistant to STZ effect.

Interestingly, similar protective effect against T1D were seen in WT mice treated with broad-spectrum antibiotics and STZ. However, addition of NOD2 ligand muramyl dipeptide reversed protection in [antibiotic + STZ] treated mice.

This study showed that NOD2 ligand, muramyl dipeptide derived from gut microbiota, contributes to T1D in STZ-treated mice.

David Usharauli

Hybrid peptides represent novel target for auto-reactive T cells in autoimmune diabetes

This week Science published intriguing study showing that in type I diabetic individuals hybrid peptides derived from two unrelated proteins represent novel auto-antigens.  

Initially, the authors showed that chemically cross-linked or synthetic peptide that is made one half of proinsulin C-peptide and another half from chromogranin A (ChgA) peptide (both β cell proteins), could activate diabetogenic mouse T cell clones.

Next, the authors showed that T cells specific for such hybrid peptides can be detected in un-manipulated diabetes susceptible NOD female mice (it would have been more informative if the authors have included data from non-susceptible WT mice as a control).

Finally, the authors showed in T cells from T1D individuals could also recognize hybrid peptide made of human proinsulin C-peptide and neuropeptide Y.

In summary, this study suggests that in T1D susceptible individuals, diabetogenic auto-antigens could be generated by fusion of peptide derived from two unrelated proteins (a side reaction of the proteolytic hydrolysis of peptide in secretory granules). Whether generation of such immunogenic hybrid peptides happens only T1D susceptible individuals remains to be determined.  

David Usharauli