Molecular mimicry to gut microbiota antigen protects against colitis but induces diabetes

Current issue of journal Cell has one very interesting but at the same time confusing research paper. In it, the authors proposed that

(a) diabetes susceptible mice strain, NOD, harbor CD8 T cells specific for microbiota antigen that cross-react with β cell antigen, IGRP, and

(b) such molecular mimicry prevents colitis but at the same time could induce diabetes.

First, the authors showed that MHC I alelle expressed in NOD mice (H2K^d) could bind IGRP_206-214 homologue derived from integrase family expressed by some gut Bacteroides species (BacIYL_36–44). 

At high dosage, such binding was functional in stimulating high affinity IGRP_206-214-specific T cells (17.4+ CD8 T cells).

Human T cells from PBMCs could apparently respond to it as well (though it is strange that it generated better stimulation index than Tetanus toxoid).

Then, the authors did the following experiment. They exposed IGRP^-/- 17.4+ TCR transgenic mice to chemical irritant (DSS) and observed that high affinity IGRP_206-214-specific T cells, 17.4+ CD8 T cells, but not low affinity ones (17.6+), could protect against colitis (I assume that they used IGRP^-/-mice to avoid diabetes development).

It appears that colitis protection depended on perforin expression by 17.4+ T cells. The authors speculated that 17.4+ CD8 T cells prevented colitis by eliminating dendritic cells laden with microbiota-derived antigen (BacIYL_36–44).

As a confirmation, the authors showed that germ-free TCR Tg NOD mice colonized with Bacteroides species expressing BacIYL_36–44 were protected against colitis.

Colitis protection was observed even in classical, adoptive naive CD4+ T cell transfer colitis model.

Interestingly, however, transfer of T cells from pre-diabetic NOD mice into germ-free NOD.scid mice colonized with Bacteroides species expressing BacIYL_36–44 did not accelerate diabetes development (here I assume DSS is required to accelerate T cells priming against IGRP by creating dysbiosis).

In summary, this study suggests the following scenario: diabetes-inducing CD8+ T cells cross-react with gut microbiota-derived antigen. When such microbiota-derived antigens become visible to T cells (during dysbiosis?) CD8+ T cells migrate to gut and eliminate dendritic cells laden with cross-reactive antigens. By eliminating DCs, other T cells are not able to induce inflammation in the gut, thus no colitis. However, the same beneficial CD8+ T cells later migrate to β cells, recognize similar looking antigen, IGRP, and mediate its destruction and diabetes.

Does such circuit makes any evolutionary sense? 

Update: Interestingly, other research group previously detected different set of gut microbiota antigens cross-reactive to IGRP_206-214. They used TCR NY8.3 transgenic NOD mice (that recognize the same IGRP epitope) and found that these CD8 T cells cross-reacted with IGRP_206–214 homologous peptide, W15944, derived from L. goodfellowii, a member of the phylum Fusobacteria (gram-negative anaerobe), a human and NOD mouse oral commensal. 

posted by David Usharauli   

Prevalence of inhibitory LPS within gut microflora could underlie hygiene hypothesis

This week prestigious journal Cell published seminal microbiome study that could explain hygiene hypothesis that suggests that "microbial cleanliness" in developed countries predisposes individuals to immunopathologies such as allergy, multiple sclerosis and other autoimmune diseases. 

This study found that gut microflora in babies from Finland and Estonia, but not from Russian Karelia, are enriched in gut bacteria with inhibitory LPS that failed to properly "educate" newborns innate immune system thus predisposing them to higher incidence of immunopathologies.

The first finding was that microbiota in babies from Finland, but not from Russian Karelia, were enriched in Bacteroides. Now this fact by itself isn't too surprising. 

The second finding was that lipid A component of LPS from these Bacteroides [unlike lipid A component of LPS from E. coli] species were non-stimulatory in TLR4 assay. In fact, molecular analysis showed that Bacteroides harbored tetra- and penta-acylated lipid A structures, as opposed to the hexa-acylated lipid A seen in E. coli. Such structural modification converted Bacteroides lipid A into totally non-stimulatory ligand.

In fact, Bacteroides derived lipid A was inhibitory when combined with stimulatory, E.coli derived lipid A [LPS tolerance assay, where primary exposure to E. coli LPS makes responding cell refractory to secondary exposure].

Finally, third finding was that presence of non-stimulatory lipid A had immunological consequences since it failed to reduce incidence of diabetes in NOD mice [whereas lipid A from E. coli could, as expected].  

In summary, this important study has provided one of the first definite molecular evidence underlying hygiene hypothesis and suggested the path for its prevention.

David Usharauli