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Skin resident memory and resident regulatory T cells

Guest Felix J. Tapia


blog-0407500001350343264.jpgRegulatory T cells (Treg) play an important role in controlling ongoing immune responses and silencing exacerbated immune responses. Various subsets of regulatory T cell populations have been identified and are subdivided based on their surrounding microenvironment, expression of activation molecules, production of cytokines, and mechanisms of action. Briefly, naturally occurring thymic-derived CD4+CD25+ Treg are characterized by their constitutive expression of the transcription factor FOXP3, while antigen-induced Treg are mainly identified by their expression of immuneregulatory cytokines such as IL-10 and transforming growth factor (TGF)-β.

Recently, a think-tank group working on the early events of the skin immune responses, including the role of T cell mediated memory response, has described a population of antigen-stimulated T cells known as resident memory T Cell (T[sub]RM[/sub]). These cells protect against subsequent skin infections or inflammations. The team of researchers is lead by Thomas S. Kupper from Brigham and Women's Hospital and the Harvard Skin Disease Research Center. The finding of these T[sub]RM[/sub] is a breakthrough and a paradigm rupture since it has long been thought that protective memory resides in blood and secondary lymphoid organs (ie. lymph nodes).

First, they demonstrated that after infection with vaccinia virus (VACV), the epidermis is invaded by abundant numbers of CD8+ skin T[sub]RM[/sub] cells that were generated from the draining lymph nodes and are capable of rapidly invading the whole skin. T[sub]RM[/sub] are potent effector cells, more than circulating central memory T cells (T[sub]CM[/sub]), at providing rapid long-term protection against cutaneous re-infection. In contrast, T[sub]CM[/sub] circulate between blood and distant lymph nodes, and some enter these secondary lymphoid organs and differentiate into T[sub]EM[/sub] that home to distal sites, maintaining central immunological memory.

Using [url="http://wiki.answers.com/Q/What_is_parabiotic_mice"]parabiotic mice[/url], the researchers showed that circulating CD8+ T[sub]CM[/sub] and CD8+ skin T[sub]RM[/sub] cells are both generated after skin infection; however, CD8+ T[sub]CM[/sub] cells recirculated between blood and lymph nodes whereas T[sub]RM[/sub] cells remain in the skin.. Mice with skin T[sub]RM[/sub] cells rapidly cleared a subsequent re-infection with VACV whereas mice with circulating T[sub]CM[/sub], but no skin T[sub]RM[/sub] cells, showed greatly impaired viral cure, indicating that T[sub]RM[/sub] cells provide superior protection.

These results have important implications for our understanding of protective immune memory at epithelial sites, and suggest new therapeutic strategies for infectious skin diseases.

A recent study by the same group demonstrated that resting (steady state) Langerhans cells, the skin prototypes of dendritic cells, induced the activation and proliferation o skin resident regulatory T cells (Treg), that prevent the immune system from attacking normal skin. However, in the presence of a pathogen, Langerhans cells induced the proliferation of skin resident T[sub]EM[/sub], inducing immunity by limiting T reg. This study further characterize the role of epidermal dendritic cells in immunity and tolerance, identifying the specific T lymphocytes involves in each process.

Jiang X, Clark RA, Liu L, Wagers AJ, Fuhlbrigge RC, Kupper TS. Skin infection geenerates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 2012, 483:227-232.

Seneschal J, Clark RA, Gehad A, Baecher-Allan CM, Kupper TS. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 2012, 36: 1-12.

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Dr. Phillip McKee


Many thanks for this wonderful blog. I knew I was going to learn a lot from you. The interesting thing for me is that when I was in medical school, the distinction between B-cells and T-cells had just been made. What a lot has happened since then!
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