Carbon-derived environmental pollutants induce atopic dermatitis-associated skin itch via Artemin

It has been recognized that various organic [carbon-derived] pollutants activate the transcription factor AhR (aryl hydrocarbon receptor). AhR initiate the expression of genes encoding detoxification enzymes in response to xenobiotics (foreign chemicals, not ordinarily found in the body). Such response, if overwhelmed, could lead to pathology. As an example, studies have revealed a relationship between air pollution and the prevalence and exacerbation of atopic dermatitis (AD), a chronic, itchy skin inflammation. 

New study in Nature Immunology showed that AhR signaling in response to organic pollutants initiates skin itch by producing neurotrophic factor, Artemin.

Initially the authors created mice that would constitutively express Ahr in skin epithelial cells (AhR-CA mice). These mice developed more itchy skin and their skin contained more of inflammatory cytokines and cells.

In addition, skin of Ahr-CA mice contained more abundant network of neurons associated with itching behavior (TRPV1+ neurons).

The authors found that neurothropic factor Artemin was highly expressed in skin of Ahr-CA mice.

Depletion of Artemin via antibody injection reduced itching behavior and skin epithelial neuronal density.

Finally, mice lacking Ahr in skin epithelial cells (approximately 70% efficiency for the deletion of Ahr specifically in the epidermis) expressed reduced level of Artemin and display less skin inflammation in response to organic pollutants (though skin-specific Artemin deficiency would have been more valuable here).

In summary, this study suggests that air pollution by carbon derivatives, such as diesel exhaust particles, could initiate manifestation of atopic dermatitis by hyper-activation of the skin Ahr function.

David Usharauli

Part of AIRE KO phenotype (APECED in humans) is dictated by gamma-delta T Cells

AIRE deficiency in mice (human equivalent of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, APECED) leads to chronic tissue immunopathology. Due to role of AIRE in generation of thymic FOXP3+ T regulatory cells, it is believed that underlying cause for tissue pathology on AIRE KO background is a lack of Tregs specific for tissue specific antigens.

However, the new data in journal Immunity from the research group which pioneered the study of AIRE suggest that part of AIRE KO phenotype is dictated by changes in γδ T cells secreting cytokine IL-17.

The authors observed that while total γδ T cells numbers were not different WT and AIRE KO littermates, γδ T cells expressing IL-17 were up-regulated in AIRE KO mice.

Interestingly, AIRE KO mice also deficient for γδ T cells (double deficient mice) showed marked resistance to immunopathology to such tissues as eyes and lungs (though other target tissues were still susceptible).

At the cellular level, there was a significant increase in IL-23r-GFP+ γδ T cells (marker for IL-17+ γδ+ T cells) in retinal tissue in AIRE KO mice at early age, even before tissue pathology was apparent. Of note, the fact that IL-17+ γδ+ T cells are present in retinal tissue in WT mice as well points to its role in physiological processes, not just in pathology).

In summary, this study indicates that subset of γδ T cells could play a leading role in initiating certain tissue pathology on AIRE KO background.

It is not clear, however, how changes in γδ T cell compartment relates to changes in Treg compartment on AIRE KO mice. Also, the role of tissue microbiota and its changes in KOs should be considered to fully understand immunopathologies. In this paper the authors provided the answers to neither to these two relevant topics.

David Usharauli

A minor subset within CD11c+ dendritic cells is primarily responsible for peripheral Treg expansion

FOXP3+ Tregs play a major role in tolerance maintenance in the periphery. Most of FOXP3+ Tregs are thymus derived. Thymus is a specialized lymphoid tissue that generates novel T cells from their bone marrow precursors. The question whether naive T cells could convert into FOXP3+ Tregs in the periphery has not been settled. 

It is believed that a "steady-state" condition favors FOXP3+ Tregs conversion in the periphery. However, a concept of "steady-state" is an arbitrary one, defined as absence of deliberate immunization or experimentally observed infection. In fact, whether "steady-state" truly exist is an open question as well.

Why this matters? Almost everyone agrees that in absence of so called "steady-state" naive T cells would convert into effector T cells rather than into FOXP3+ Tregs following antigen recognition. For example, if one wants to generate new FOXP3+ Tregs specific for particular antigen to treat autoimmune diseases, this task would be almost impossible to achieve if condition of "steady-state" does not actually exist in the body [from T cells' "point of view"]. 

Also, what cell types are responsible for that supposed FOXP3+ Tregs conversion? A new study in Immunity clarified this question somewhat. It showed that even in "steady-state" condition only minor subset of DCs within CD11c+ population defined by DEC205/CD8 expression were responsible for FOXP3+ Tregs "conversion" in T cell-replete mice [which harbor endogenous FOXP3+ Tregs].

For this study, the authors have used chimeric anti-DEC205 Ab [or anti-CD11c chimeric Ab as a control] that incorporate antigen of interest [MOG or OVA]. When injected into mice chimeric anti-DEC205 Ab, but not control, could "convert" naive MOG or OVA-specific T cells into FOXP3+ Tregs.

It appeared that DEC205+ CD11c+ DCs were also primarily BTLA+ and its expression were required for FOXP3+ Tregs induction.

Interestingly, the authors proposed that BTLA to HVEM signaling in naive T cells up-regulated CD5 and permitted FOXP3+ Tregs conversion even in presence of inflammatory cytokines such as IL-4 and IL-6.  

However, in my view, such mechanism of FOXP3+ Tregs conversion even in presence of inflammation sounds counter-intuitive. Wouldn't it also induce FOXP3+ Tregs conversion from naive T cells specific for nonself antigen derived from pathogens during inflammation? Otherwise, how can system make sure that only self antigens are presented by DEC205+ DCs? The authors could only admit that this tolerance mechanism somehow only affects "self and tolerizing antigens". Also, what about endogenous FOXP3+ Tregs in these mice? Is it possible that endogenous thymus FOXP3+ Tregs are involved in assisting in FOXP3+ Tregs conversion, rather than DEC205+ DCs doing it alone from scratch? If so, implications are very different.  

David Usharauli