A window of opportunity

Credit: S. Bradbrook/NPG

Immune tolerance to commensal microbiota needs to be established at each barrier site. Reporting in Immunity, Rosenblum and colleagues show that immune tolerance to skin commensals requires early bacterial colonization and an influx of activated regulatory T (T_Reg) cells into neonatal skin.

The authors generated a mouse model in which the skin commensal Staphylococcus epidermidis was engineered to express the peptide antigen 2W (Epi-2W) linked to a fluorescent protein. The Epi-2W strain could stably colonize mouse skin without causing local inflammation, and colonized mice had increased numbers of activated 2W-specific CD4⁺ T cells in both the skin-draining lymph nodes (SDLNs) and the spleen. Thus, commensal antigens were recognized both locally and systemically across an intact skin barrier.

Next, 6-week-old adult mice were colonized with Epi-2W and, 3–4 weeks later, these mice were challenged with Epi-2W in combination with light scratching of the skin. This mimics the increased exposure to commensal antigens that occurs in response to incidental skin trauma — a situation in which immune tolerance needs to be active. Adult mice that were pre-colonized with Epi-2W and control mice that were not pre-colonized showed a similar increase in skin inflammation after challenge with Epi-2W. However, when mice were colonized on postnatal day 7 and challenged with Epi-2W in adult life, histological skin inflammation and neutrophilic infiltration were reduced compared with age-matched controls without prior Epi-2W exposure. Hence, microbial skin colonization in the neonatal period promotes tolerance to commensal bacteria.

neonatal T_Reg cells were highly activated compared with T_Reg cells in adult skin

The authors found that, between postnatal days 6 and 13, there was a marked increase of αβ T cells in the skin, of which T_Reg cells accounted for over 80% of CD4⁺ T cells compared with around 50% in adult skin. By contrast, other T cell subsets did not accumulate during this period. Furthermore, the neonatal T_Reg cells were highly activated compared with T_Reg cells in adult skin. This early influx of T_Reg cells was not seen in the intestinal lamina propria or SDLNs and therefore seems to be unique to the skin.

Finally, the authors investigated whether the accumulation of T_Reg cells in neonatal skin is required to establish tolerance to skin commensals. Indeed, transiently blocking the migration of T_Reg cells into the skin in neonatal mice, before neonatal colonization with Epi-2W, led to increased skin inflammation after challenge with Epi-2W in adult mice. This inflammation was associated with increased numbers of antigen-specific effector CD4⁺ T cells in the SDLNs and a reduction of antigen-specific T_Reg cells in the SDLNs and skin.

In summary, establishment of tolerance to commensal skin microorganisms depends on early bacterial colonization and an influx of T_Reg cells into neonatal skin.