Saturday, September 16, 2017

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 


Tuesday, September 12, 2017

It is really hard to replicate human autoimmune diseases in mice

A new study in PNAS highlights the challenges scientists face when trying to reproduce human diseases in mice.  

Here, the authors tried to reproduce human type I diabetes by creating humanized mice by transplantation of HLA-DQ8+ human fetal thymus and CD34+ stem cells into immunodeficient mice (to recreate human immune system in mouse) followed by transfer of autologous [hu-mice]-derived HLA-DQ8/insulin-B:9–23 specific TCR transduced human CD4+ T cells and followed by two successive low doses of streptozotocin (a chemical to damage islet β cells and release auto-antigen).

However, even these steps were not enough to induce diabetes in hu-mice. Only immunization with insulin B:9–23 peptide + adjuvant (HLA class II-restricted T-cell response to InsB:9–23 peptide is highly associated with T1D in humans) in addition to above mentioned "conditioning" were able to induce diabetes in hu-mice.

No one really knows how autoimmune diseases are initiated in humans and these study shows that it is really hard to "reproduce" it in mice. Of course, it is not known what factors could play the role of "streptozotocin" and "B:9–23 peptide immunization" in natural context in humans. 

posted by David Usharauli

Friday, September 8, 2017

Loss of microbiota depletes cross-reactive Foxp3+ Tregs leading to selective immunopathologies

Check out our follow-up manuscript in PeerJ Preprints that provides a brief guide to SPIRAL, a novel interpretive framework that demonstrates the central role of microbiota-Treg axis in the initiation of immune disorders.

Kamala T, Usharauli D. (2017)
Loss of microbiota depletes cross-reactive Foxp3+ Tregs leading to selective immunopathologies.
PeerJ Preprints 5:e3237v1
The 'Hygiene hypothesis', a cornerstone model to account for the role of exogenous pathogens and later of endogenous microbiota in immune disorders, is currently presumed to operate at the innate immunity and metabolite levels to properly 'educate' the immune system. Doing so however fails to satisfactorily account for the antigen-specific nature of such disorders. SPIRAL is a novel interpretive framework that resolves this dilemma. It represents the periodic table of cross-reactive Foxp3+ regulatory T cell (Treg) epitopes selected from commensal microbiota over evolutionary time to mediate self-nonself discrimination and effector class regulation. Here, we utilize the SPIRAL's predictive power to provide a mechanistic antigen-specific basis for the initiation of allergies and autoimmune diseases as well as for the failure to mount effective anti-tumor and vaccine responses through selective loss of microbiota and corresponding cross-reactive Foxp3+ Tregs.