Wednesday, November 18, 2015

Time dictates tolerance to skin microbiota

To study relationship between skin microbiota and skin immune response, the authors modified human skin commensal microbe, Staphylococcus Epidermidis, by introducing into it a nominal peptide antigen 2W [Epi-2W]. This allowed tracking of 2W-tetramer+ CD4 T cells. Primary application of Epi-2W to adult mouse skin for the first time induced recruitment of 2W-tetramer+ CD4 T cells in skin draining lymph nodes without inducing any skin inflammation [proof-of-principle experiment].

Next, the authors tested how adult mice immune system would respond to secondary skin challenge with Epi-2W. They showed that adult mice exposed to skin Epi-2W do not develop tolerance to it upon secondary challenge. These mice displayed (a) skin inflammation

(b) no accumulation of 2W-tetramer+ Foxp3CD4 T cells, implying failure of tolerance.

However, if skin of neonatal day 7 mice were exposed to Epi-2W and later challenged again, these mice showed (a) minimal skin inflammation 

(b) and robust accumulation of 2W-tetramer+ Foxp3CD4 T cells, implying active tolerance to Epi-2W.

Followup experiments found that between neonatal day 6-13 there was a sudden increase of thymic Foxp3CD4 T cell numbers specifically in skin.

Finally, the authors showed that when this increase of neonatal skin Foxp3CD4 T cells were blocked, it resulted in tolerance failure towards Epi-2W challenge and skin inflammation.

In summary, these results indicate that timely [neonatal] exposure to skin commensals is necessary to establish antigen-specific Foxp3CD4 T cell-mediated immune tolerance to skin microbiota and to prevent pathological skin inflammation later on. It is possible that in near future human neonates will be artificially exposed to the defined sets of human commensals via skin application, nasal inhalations and oral application to specifically train their neonatal immune system for tolerance towards commensals and hence better distinguish between beneficial and pathogenic microorganims.

David Usharauli

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