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


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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    ABSTRACT: Tissue-resident memory T cells (TRM) reside in barrier tissues and provide local immediate protective immunity. Here, we show that the salivary gland (SG) most-effectively induces CD8(+) and CD4(+) TRM cells against murine cytomegalovirus (MCMV), which persists in and spreads from this organ. TRM generation depended on local antigen for CD4(+), but not CD8(+), TRM cells, highlighting major differences in T cell subset-specific demands for TRM development. CMV-specific CD8(+) T cells fail to control virus replication upon primary infection in the SG due to CMV-induced MHC I downregulation in glandular epithelial cells. Using intraglandular infection, we challenge this notion and demonstrate that memory CD8(+) T cells confer immediate protection against locally introduced MCMV despite active viral immune evasion, owing to early viral tropism to cells that largely withstand MHC I downregulation. Thus, we unravel a yet-unappreciated role for memory CD8(+) T cells in protecting mucosal tissues against CMV infection.
    Full-text · Article · Nov 2015 · Cell Reports
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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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    ABSTRACT: Heterologous immunity refers to the phenomenon whereby a history of an immune response against one pathogen can provide a level of immunity to a second unrelated pathogen. Previous investigations have shown that heterologous immunity is not necessarily reciprocal, such as in the case of vaccinia virus (VACV). Replication of VACV is reduced in mice immune to a variety of pathogens, while VACV fails to induce immunity to several of the same pathogens, including lymphocytic choriomeningitis virus (LCMV). Here we examine the lack of reciprocity of heterologous immunity between VACV and LCMV and find that they induce qualitatively different memory CD8 T cells. However, depending on the repertoire of an individual host, VACV can provide protection against LCMV simply by experimentally amplifying the quantity of T cells cross-reactive with the two viruses. Thus, one cause for lack of reciprocity is differences in the frequencies of cross-reactive T cells in immune hosts. Copyright © 2015 Elsevier Inc. All rights reserved.
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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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    ABSTRACT: Translational research programs offer incredible opportunities to bring cutting edge science into clinical practice. To facilitate these medical advances, funding agencies are increasingly focusing on a translational "payoff" within grant applications and larger programs. As this is the underlying promise of biomedical research-delivering advances to public health to improve the quality of life-such strategic initiatives are paramount. However, the process of taking experimental observations between model systems and human subjects can be extraordinarily frustrating. We brought together the collective expertise of our mouse and human immunology research programs to reverse engineer a clinical observation into a mouse model system. Our goal was to model (in mice) the age-related impaired delayed-type hypersensitivity response observed in humans, and then evaluate the efficacy of interventions to improve cutaneous immunity. We report here on what worked, what didn't, and what we learned along the way.
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