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 (H2Kd) could bind IGRP206-214 homologue derived from integrase family expressed by some gut Bacteroides species (BacIYL36–44).
At high dosage, such binding was functional in stimulating high affinity IGRP206-214-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 IGRP206-214-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 (BacIYL36–44).
As a confirmation, the authors showed that germ-free TCR Tg NOD mice colonized with Bacteroides species expressing BacIYL36–44 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 BacIYL36–44 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 IGRP206-214. They used TCR NY8.3 transgenic NOD mice (that recognize the same IGRP epitope) and found that these CD8 T cells cross-reacted with IGRP206–214 homologous peptide, W15944, derived from L. goodfellowii, a member of the phylum Fusobacteria (gram-negative anaerobe), a human and NOD mouse oral commensal.
At high dosage, such binding was functional in stimulating high affinity IGRP206-214-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 IGRP206-214-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 (BacIYL36–44).
As a confirmation, the authors showed that germ-free TCR Tg NOD mice colonized with Bacteroides species expressing BacIYL36–44 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 BacIYL36–44 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 IGRP206-214. They used TCR NY8.3 transgenic NOD mice (that recognize the same IGRP epitope) and found that these CD8 T cells cross-reacted with IGRP206–214 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
