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. 2012 Feb 29;483(7388):227-31.
doi: 10.1038/nature10851.

Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity

Xiaodong Jiang  1 , Rachael A Clark, Luzheng Liu, Amy J Wagers, Robert C Fuhlbrigge, Thomas S Kupper
Affiliations

Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity

Xiaodong Jiang et al. Nature. .

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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Conflict of interest statement

The authors have no conflicting financial interests.

Figures

Figure 1
Figure 1. CD4+ T cells and IFN-γ are not required for acute recruitment of CD8+ T cells to VACV-infected skin
Pentamer+ CD8+ T cells in dLN and infected skin 7 days after VACV infection. a, The percentages of pentamer+ CD8+ T cells are shown (excluding CD19+ cells before flow cytometry analysis). b, The numbers of pentamer+ CD8+ T cells in infected skin. c, d, The kinetic infiltration of Thy1.1+ OT-I and CD45.1+ OT-II cells to infected skin after their co-transfer to naive mice. e-g, The numbers of OT-I cells in infected skin 7 days after infection in the absence of CD4, IFN-γ or FucT IV/VII, respectively. All data above are representative of at least three independent experiments (n = 5 mice/time point/group). b, d-g, Error bars, s.e.m.; **, P<0.01; N.S., not significant. WT, wild-type; KO, knockout; dLN, draining lymph node.
Figure 2
Figure 2. CD8+ TCM re-circulate quickly between parabiotic mice, but skin CD8+ TRM remain in place long term
a, 2×106 Thy1.1+ OT-I cells were intravenously transferred into Thy1.2+ mice 1 day prior to 2×106 PFU VACV-Ova skin scarification. 30 days after infection, OT-I-bearing mice were joined surgically with naïve Thy1.2+ mice to create parabiotic mice. At indicated time points after surgery, parabiotic mice were separated and lymphoid tissues and skin were harvested to examine OT-I cells. b, The percentages of memory OT-I cells in the indicated lymphoid tissues between parabiotic mice 2 and 8 weeks after surgery were examined. c, The percentages of OT-I TRM in the skin of parabiotic and control mice over time were also examined. d, The numbers of OT-I TCM in dLN of parabiotic mice 8 weeks after surgery. e, The numbers of OT-I TRM in the skin of parabiotic and control mice 8 weeks after surgery. b-e, Data are representative of three independent experiments (n = 5 mice/time point/group). d,e, Error bars, s.e.m.; N.S., not significant. f, Immunofluorescence of OT-I cells in infected skin sites 45 days after infection. Sections were stained for nuclei (DAPI, blue) and Thy1.1 (red). n = 15 sections from 5 mice. Two representative sites are shown. mLN, mesenteric lymph node; dLN, draining lymph node; iLN, inguinal lymph node; DAPI, 4′,6-diamidino-2-phenylindole.
Figure 3
Figure 3. Skin CD8+ TRM are superior to both antibody and TCM at protecting against re-infection
a, µMT mice with OT-I transfer and VACV-Ova skin infection were used to create OT-I : normal parabiotic mice as before. 8 weeks after surgery, parabiotic mice were separated. 2 weeks later, separated mice were challenged with VACV-Ova on the skin. Half mice were injected daily with FTY720. b, 6 days after challenge, skin viral load was assayed by qPCR. c, In separate experiments, µMT mice without OT-I transfer but with VACV skin infection were used to create immunized : unimmunized parabiotic mice. 4 weeks after surgery, the same VACV skin challenge protocol was applied. d-f, 6, 14, or 26 days after challenge, viral load was assayed. The results from duplicate qPCR runs are plotted. Horizontal bars indicate the mean. Data are representative of two independent experiments (n = 5 mice/group). **, P<0.01; N.S., not significant.
Figure 4
Figure 4. Skin CD8+ TRM also accumulate in unimmunized site after skin infection and are highly effective at eliminating virus
a, 2×106 Thy1.1+ OT-I cells were intravenously transferred into Thy1.2+ mice 1 day prior to 2×106 PFU VACV-Ova skin scarification (s.s.). The numbers of OT-I cells in infected and uninfected skin were enumerated over time. b, The left ears of OT-I-infused B6 mice were infected with VACV-Ova. 20 and 30 days later, some of mice were challenged with 2×106 PFU VACV-Ova on the tail and flank skin, respectively. All infection routes were s.s.. 30 days after challenge, Thy1.1+ OT-I cells in uninfected right ears were examined. c, The percentages of Thy1.1+ OT-I cells in uninfected right ears. d, The numbers of Thy1.1+ OT-I cells in uninfected right ears. Error bars, s.e.m. e, µMT mice were infected with VACV either by s.s. on one ear or intraperitoneal (i.p.) injection. 7 or 30 days later, mice were challenge with VACV on both ears via s.s. route. Daily i.p. injection of FTY720 was performed. f, g, 6 days later, viral loads in both infected and uninfected ears were measured. The mean and s.d. from triplicate qPCR runs are plotted. Data are representative of three independent experiments (n = 5 mice/group). **, P<0.01.
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Comment in

  • T cell memory: Skin-deep memory.
    Bird L. Bird L. Nat Rev Immunol. 2012 Mar 22;12(4):230-1. doi: 10.1038/nri3201. Nat Rev Immunol. 2012. PMID: 22437929 No abstract available.

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