Wednesday, July 26, 2017

IBD converts tolerant antigens into immunogenic

Inflammatory bowel disease (IBD) is a pathological condition wherein body's immune cells wrongly attack its own or commensal microbiota-derived antigens that initiates a vicious cycles of permanent inflammation.
However, it is still not clear whether immune system attacks "new" antigens from microbiota or simply it loses adaptive tolerance to "old" ones. 
New study in Science Immunology tried to answer it to the extent it was possible to do in mouse model.
First, the authors generated IBD condition in mice by treating them with DSS + anti-IL10R. Keep in mind this is highly artificial model. Then, they transferred naïve T cells from previously established transgenic T cell lines specific for unknown commensal antigens that were known to drive Treg phenotype. Naïve T cells transferred into control WT mice generated Tregs while the naïve T cells transferred into IBD-conditioned mice preferably developed into effector T cells.
When analyzed for antigen specificity, the authors found that transgenic naïve T cells were reactive to antigens derived from Helicobacter species that have expanded during IBD-conditioning.
In vivo studies also confirmed that Helicobacter species could induce Treg generation from naïve transgenic T cells in "normal" condition.
Interestingly, transfer of T cells specific for other microbiota species that also underwent expansion during IBD-conditioning did not produce T cell expansion.
Finally, transfer of Treg-TCR transgenic naïve T cells into RAG-KO mice produced IBD when co-injected with Helicobacter species.
What these data indicate? In my view the authors made one correct and one wrong interpretation. First, they were correct to conclude that T cell response to IBD could be directed to "old" microbiota antigens rather than "new" never before seen microbiota-derived antigens. So basically in IBD we are losing tolerance rather than gaining immunity to microbiota antigens.
However, they made wrong conclusion that naïve T cells are converted into Tregs in vivo based on context (normal versus IBD). In their study loss of Treg generation is inhibited either during IBD-conditioning or in RAG KO hosts which could argue alternatively that such outcome has to do with failure of naïve T cells to interact with existing Tregs specific for the same or similar antigens in these scenarios (IBD or RAG-KO).
posted by David Usharauli

Sunday, July 16, 2017

Identification of prostate-antigen specific natural Tregs (in mice)

Foxp3+ Tregs are central player in maintaining tolerance to self and other environmental antigens. However, till to this date we know little of their antigen specificity. It is because unlike conventional CD4+ T cells, Tregs do not secrete [upon antigen recognition] any cytokine that uniquely identifies them. The best marker is still Foxp3 molecule, an intracellular transcription factor.   

So it is always interesting to see new study that could identify Treg epitope, such as this new paper in Immunity that provided evidence that in mice peptide spanning residues 646–658 of prostate-specific TRPM8 channel-associated factor 3 protein (Tcaf3) is a natural epitope for thymic MJ23 TCR transgenic Treg development.

The authors showed that development of MJ23+ Tregs from adoptively transferred MJ23+ thymocytes (un-differentiated T cells) were only supported in hosts expressing intact Tcaf3 (and not in Tcaf3 KO mice).   

Next, using sensitive tetramer based antigen-specific T cell detection, the authors showed that WT mice also harbored Tcaf3[646–658]-tetramer specific T cells that were enriched in Tregs compared to other antigen-specific T cells (2W1S). Interestingly, Aire-KO mice which do not efficiently express peripheral antigens in the thymus harbored reduced numbers of Tcaf3[646–658]-tetramer specific Tregs.

Finally, the authors showed that prostate tissue from Aire KO mice harbored significantly more Tcaf3[646–658]-tetramer specific Tregs compared to prostate tissue from normal mice. I found these particular results problematic because should not normal mice prostate supposed to contain Tregs to prevent autoimmunity? Or are Tregs keeping autoreactive T cells in check in draining lymph nodes? 

In summary, this study showed that in mice prostate-specific Tcaf3[646–658] epitope is a natural ligand that selects Tregs in a Aire-dependent manner.

posted by David Usharauli


Monday, July 10, 2017

How Foxp3+ Tregs and microbiota work together to control immune system

Check out our new paper in PeerJ Preprints that unlocks the mystery of how Foxp3+ regulatory T cells work that enables proper immune functioning.

Usharauli D, Kamala T. (2017) An identical mechanism governs self-nonself discrimination and effector class regulation. PeerJ  Preprints 5:e3081v1

Prevailing immunological dogma dictates self-nonself discrimination, meaning to respond or not, and effector class regulation, meaning choosing the most effective response, are two separate decisions the immune system makes when faced with a new antigen. Representing a cardinal departure from the past, our model instead predicts both self-nonself discrimination and effector class regulation are in fact one and the same process controlled by Foxp3+ regulatory T cells (Tregs) whose antigen-specific repertoire is entirely maintained by commensal microbiota-derived cross-reactive antigens.
posted by David Usharauli