Article

Jiang X, Clark RA, Liu L et al.Skin infection generates non-migratory memory CD8+T RM cells providing global skin immunity. Nature 483:227-231

Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 03/2012; 483(7388):227-31. DOI: 10.1038/nature10851
Source: PubMed

ABSTRACT

Protective T-cell memory has long been thought to reside in blood and lymph nodes, but recently the concept of immune memory in peripheral tissues mediated by resident memory T (T(RM)) cells has been proposed. Here we show in mice that localized vaccinia virus (VACV) skin infection generates long-lived non-recirculating CD8(+) skin T(RM) cells that reside within the entire skin. These skin T(RM) cells are potent effector cells, and are superior to circulating central memory T (T(CM)) cells at providing rapid long-term protection against cutaneous re-infection. We find that CD8(+) T cells are rapidly recruited to skin after acute VACV infection. CD8(+) T-cell recruitment to skin is independent of CD4(+) T cells and interferon-γ, but requires the expression of E- and P-selectin ligands by CD8(+) T cells. Using parabiotic mice, we further show that circulating CD8(+) T(CM) and CD8(+) skin T(RM) cells are both generated after skin infection; however, CD8(+) T(CM) cells recirculate between blood and lymph nodes whereas T(RM) cells remain in the skin. Cutaneous CD8(+) T(RM) cells produce effector cytokines and persist for at least 6 months after infection. Mice with CD8(+) skin T(RM) cells rapidly cleared a subsequent re-infection with VACV whereas mice with circulating T(CM) but no skin T(RM) cells showed greatly impaired viral clearance, indicating that T(RM) cells provide superior protection. Finally, we show that T(RM) cells generated as a result of localized VACV skin infection reside not only in the site of infection, but also populate the entire skin surface and remain present for many months. Repeated re-infections lead to progressive accumulation of highly protective T(RM) cells in non-involved skin. These findings have important implications for our understanding of protective immune memory at epithelial interfaces with the environment, and suggest novel strategies for vaccines that protect against tissue tropic organisms.

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    • "T EM cells lack CD62L and CCR7 but express homing molecules that enable them to enter inflamed peripheral sites and exert immediate effector functions. Whereas T EM cells can provide protection against systemic infection, their ability to contain peripheral infections is surprisingly limited (Bachmann et al., 2005; Jiang et al., 2012; Mackay et al., 2012), owing to progressive contraction and loss of tissue-homing molecules. Early blood-based studies have established the concept of circulatory immune surveillance in which memory T cells are in constant exchange with either lymphoid or non-lymphoid tissues via the circulation. "
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    • "We found that the overall frequency of IL-2þ A11R 198–205 -specific CD8 T cells was slightly lower in the protected animals (average 1.0%) than in the unprotected ones (average 1.6%), but this likely just means that the presence of higher levels of antigen was continuing to stimulate the T cells, rather than reflecting on any intrinsic T cell deficiency. Resident effector memory T cells have been reported to be important for protection against VACV in parabiotic studies (Jiang et al., 2012), and the enhanced effector function of LCMV-immune T cells resembles that of effector memory cells. This would potentially make cross-reactive LCMV-specific memory T cells better at mediating heterologous immunity as compared to the cross-reactive VACV-specific T cells with a more resting central memory cell phenotype. "
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    • "Contrast this with the situation in humans (described above), in which DTH is a measurement of long-term T cell memory that was previously generated in response to (presumed) natural exposure to an infectious pathogen, typically via the respiratory system. Upon skin inoculation with antigen, memory T cells are either resident in the tissue to respond to the challenge (likely for VZV), or are recruited to the site of challenge from the circulation (likely for MTb) (Gebhardt et al. 2009; Jiang et al. 2012 "
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