Wednesday, August 23, 2017

MHC class II epitope presentation modulates microbiota and protects against autoimmunity

It is not clear how exactly microbiota modulates host's immune system. Evidence are largely based on empirical observations and nonspecific factors secreted by microbiota. Presently very little is known if microbiota-immune system interface is also controlled at the level of antigen-specific adaptive immune system.    
New study from Diane Mathis lab published in PNAS suggests it may be the case.
Her lab studies human type I diabetes (T1D) mouse model known as NOD. NOD mice lack MHC II allele, Eα. In this study they used NOD mice expressing Eα, referred as Eα16/NOD. In mating experiments, they noticed when Eα was expressed by female but not by male parent, baby mice with NOD genotype showed significant protection from developing T1D, suggesting protection was transmitted vertically from Eα16/NOD mother to NOD pups. Interestingly, this protection was lost when pregnant mothers (dams) were treated with antibiotics pointing towards role of microbiota.

Experiments with germ-free sterile mice confirmed this observation.

In summary, this study showed that MHC class II [epitope] presentation modulates composition of microbiota in such a way to harbor species protective against T1D. Again, the authors were unable to specifically pinpoint any specific mechanism of protection, though they reported increase in Foxp3+ Treg numbers in Eα16/NOD mice compared to NOD (but found no difference in microbiota bound to IgA between mouse strains). It is likely that epitope presentation at the level of adaptive CD4 T cells contributed to development of protective environment.

posted by David



Tuesday, August 22, 2017

Does TGF-β control T cell autoimmunity independent of Tregs?

When T cells attack body's own antigens its called autoimmunity. Each and every one with the adaptive immune system carry this potential. Mostly two mechanisms prevent autoimmunity: thymic deletion of overtly auto-reactive T cells (recessive tolerance) and Foxp3+ Tregs (dominant tolerance).
Within immune system, TGF-β plays important inhibitory role at T cell level. However, since TGF-β is involved in Treg biology, it is not clear if it has Treg-independent role in preventing autoimmunity.
New paper published in PNAS tried to answer this question.
The authors used OT-II RIP-mOva mice model (on RAG KO background) in which all CD4 T cells express OVA-specific T cell receptor and pancreas express OVA protein. These mice harbor OT-II Foxp3+ Tregs and they don't develop autoimmune diabetes.

To separate effect of Tregs versus TGF-β, the authors either compared TGF-βRII-KO mice vs. Foxp3KO (both on RAG1-KO OT-II RIP-mOva background) or adoptively transferred into RAG1-KO RIP-mOVA mice either Foxp3KO OT-II or OT-II T cells expressing TGF-βRII under the control of estrogen receptor. They noticed that OT-II T cell population lacking TGF-βRII but not Foxp3 could cause or accelerate autoimmune diabetes.

These two set of experiments are central for this paper. However, contrary to the authors' conclusions, these experiments do not fully answer Tregs versus TGF-β question. The main problem is that total TGF-βRII deficiency in all CD4 T cells affects both effector and Tregs (functionally at least if not number wise) while Foxp3 deficiency only affects Tregs. That is to say that if Tregs were TGF-βRII-sufficient and effector T cells TGF-βRII-deficient outcome could be different (WT Tregs might be able to stop effector OT-II cells). Another way to separate the role of Tregs versus TGF-β would be to specifically inactivate TGF-βRII in effector T cells leaving Tregs intact.

posted by David Usharauli


Thursday, August 3, 2017

Th2A subset drives allergic phenotype in humans

TH2 cells were initially identified based on their capacity to make IL-4 and drive B cell antibody class switch recombination to IgG1  and IgE. However, more recently it became clear that TH2 cells consist of several subtypes each with its own unique specialization in particular effector function such as IL-13 or IL-25 production that have nothing to do with antibody production. 

Similarly, canonical TH2 cells were thought to be responsible for allergy phenotype in humans (and mice as well). However, new study in Science Translational Medicine suggests new subset of TH2 cells, called TH2A subset, is mainly responsible for food allergy phenotype

The authors carried out magnetic enrichment of T cells harvested from allergic patients using HLA-II tetramers. Compared to non-allergic individuals, allergic patents showed expansion of a special population of TH2 cells expressing CD161 and CD49d

Interestingly, patients undergoing antigen-specific desensitization showed selective loss of these TH2A cells.

In summary, it is clear that different subset of TH2 cells exist, some naturally others only during pathology, to deal with various foreign antigenic entities.

posted by David Usharauli