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The influence of skin microorganisms on cutaneous immunity

Key Points

  • The skin is a complex and dynamic ecosystem inhabited by many microorganisms.

  • The capacity of a given microorganism to trigger or promote disease is dependent on the state of immune activation of the host, the host's genetic predisposition and/or microorganism localization.

  • The skin microbiota can promote both innate and adaptive immunity to skin pathogens.

  • In many settings, optimal skin immunity is induced through networks of antigen-presenting cell subsets.

  • The skin is a large reservoir of tissue-resident memory T cells that can have an important role in protective immunity against pathogens.

  • Skin immune disorders in humans are associated with the enrichment of defined species of microorganisms.


The skin is a complex and dynamic ecosystem that is inhabited by many microorganisms. Recent evidence highlights the profound reliance of the skin immune system on its resident microbiota for both host defence and tissue repair. This tissue is also a primary target for infections, which are in some cases caused by normal constituents of the microbiota. In the context of infections and genetic predispositions that are associated with barrier or regulatory network defects, microorganism-induced inflammatory cycles can contribute to the initiation and/or amplification of skin disorders. This Review will discuss some of our current understanding of skin–microbiota and skin–pathogen interactions in the context of homeostasis and diseases and highlight current gaps in our understanding of the skin immune ecosystem.

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Figure 1: Contextuality of pathogenesis.
Figure 2: Structure and cellular components of the skin and control of immunity by skin-resident microorganisms.
Figure 3: Role of skin-resident dendritic cells in the induction of T cell responses to skin microorganisms.
Figure 4: Host–microorganism inflammatory circles: microorganisms can contribute to the initiation and amplification of inflammatory loops within the skin compartment.


  1. 1

    Buffie, C. G. & Pamer, E. G. Microbiota-mediated colonization resistance against intestinal pathogens. Nat. Rev. Immunol. 13, 790–801 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Otto, M. Staphylococcus epidermidis — the 'accidental' pathogen. Nat. Rev. Microbiol. 7, 555–567 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Ibrahim, F., Khan, T. & Pujalte, G. G. Bacterial skin infections. Prim. Care 42, 485–499 (2015).

    PubMed  Google Scholar 

  5. 5

    Roberts, N. & Horsley, V. Developing stratified epithelia: lessons from the epidermis and thymus. Wiley Interdiscip. Rev. Dev. Biol. 3, 389–402 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Pasparakis, M., Haase, I. & Nestle, F. O. Mechanisms regulating skin immunity and inflammation. Nat. Rev. Immunol. 14, 289–301 (2014).

    CAS  PubMed  Google Scholar 

  7. 7

    Tong, P. L. et al. The skin immune atlas: three-dimensional analysis of cutaneous leukocyte subsets by multiphoton microscopy. J. Invest. Dermatol. 135, 84–93 (2015).

    PubMed  Google Scholar 

  8. 8

    Belkaid, Y. & Segre, J. A. Dialogue between skin microbiota and immunity. Science 346, 954–959 (2014).

    CAS  PubMed  Google Scholar 

  9. 9

    Mueller, N. T., Bakacs, E., Combellick, J., Grigoryan, Z. & Dominguez-Bello, M. G. The infant microbiome development: mom matters. Trends Mol. Med. 21, 109–117 (2015).

    PubMed  Google Scholar 

  10. 10

    PrabhuDas, M. et al. Challenges in infant immunity: implications for responses to infection and vaccines. Nat. Immunol. 12, 189–194 (2011).

    CAS  PubMed  Google Scholar 

  11. 11

    Oh, J., Conlan, S., Polley, E. C., Segre, J. A. & Kong, H. H. Shifts in human skin and nares microbiota of healthy children and adults. Genome Med. 4, 77 (2012).

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Si, J., Lee, S., Park, J. M., Sung, J. & Ko, G. Genetic associations and shared environmental effects on the skin microbiome of Korean twins. BMC Genomics 16, 992 (2015).

    PubMed  PubMed Central  Google Scholar 

  13. 13

    Scharschmidt, T. C. & Fischbach, M. A. What lives on our skin: ecology, genomics and therapeutic opportunities of the skin microbiome. Drug Discov. Today Dis. Mech. 10, pii: e83-e89 (2013).

    Google Scholar 

  14. 14

    Bouslimani, A. et al. Molecular cartography of the human skin surface in 3D. Proc. Natl Acad. Sci. USA 112, E2120–E2129 (2015).

    CAS  PubMed  Google Scholar 

  15. 15

    Grice, E. A. et al. Topographical and temporal diversity of the human skin microbiome. Science 324, 1190–1192 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Costello, E. K. et al. Bacterial community variation in human body habitats across space and time. Science 326, 1694–1697 (2009). References 15 and 16 reveal that the composition of the skin microbiota is site specific.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Song, S. J. et al. Cohabiting family members share microbiota with one another and with their dogs. eLife 2, e00458 (2013).

    PubMed  PubMed Central  Google Scholar 

  18. 18

    Lai, Y. et al. Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nat. Med. 15, 1377–1382 (2009). This paper shows that a defined molecule produced by a commensal can indirectly promote repair.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Naik, S. et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115–1119 (2012). This study reveals that the mirobiota can promote adaptive immunity in the skin.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Gallo, R. L. & Hooper, L. V. Epithelial antimicrobial defence of the skin and intestine. Nat. Rev. Immunol. 12, 503–516 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Nagy, I. et al. Propionibacterium acnes and lipopolysaccharide induce the expression of antimicrobial peptides and proinflammatory cytokines/chemokines in human sebocytes. Microbes Infect. 8, 2195–2205 (2006).

    CAS  PubMed  Google Scholar 

  22. 22

    Chehoud, C. et al. Complement modulates the cutaneous microbiome and inflammatory milieu. Proc. Natl Acad. Sci. USA 110, 15061–15066 (2013).

    CAS  PubMed  Google Scholar 

  23. 23

    Verhulst, N. O. et al. Composition of human skin microbiota affects attractiveness to malaria mosquitoes. PLoS ONE 6, e28991 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Zhang, X., Crippen, T. L., Coates, C. J., Wood, T. K. & Tomberlin, J. K. Effect of quorum sensing by Staphylococcus epidermidis on the attraction response of female adult yellow fever mosquitoes, Aedes aegypti aegypti (Linnaeus) (Diptera: Culicidae), to a blood-feeding source. PLoS ONE 10, e0143950 (2015).

    PubMed  PubMed Central  Google Scholar 

  25. 25

    Naik, S. et al. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520, 104–108 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Iwasaki, A. & Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 16, 343–353 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Hall, J. A. et al. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29, 637–649 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Volz, T. et al. Nonpathogenic bacteria alleviating atopic dermatitis inflammation induce IL-10-producing dendritic cells and regulatory Tr1 cells. J. Invest. Dermatol. 134, 96–104 (2014).

    CAS  PubMed  Google Scholar 

  30. 30

    Laborel-Preneron, E. et al. Effects of the Staphylococcus aureus and Staphylococcus epidermidis secretomes isolated from the skin microbiota of atopic children on CD4+ T cell activation. PLoS ONE 10, e0141067 (2015).

    PubMed  PubMed Central  Google Scholar 

  31. 31

    Skabytska, Y. et al. Cutaneous innate immune sensing of Toll-like receptor 2–6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells. Immunity 41, 762–775 (2014).

    CAS  PubMed  Google Scholar 

  32. 32

    Yockey, L. J. et al. The absence of a microbiota enhances TSLP expression in mice with defective skin barrier but does not affect the severity of their allergic inflammation. J. Invest. Dermatol. 133, 2714–2721 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Bantz, S. K., Zhu, Z. & Zheng, T. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. J. Clin. Cell Immunol. 5, pii:202 (2014).

    Google Scholar 

  34. 34

    Zhang, L. J. et al. Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 347, 67–71 (2015). This paper reveals a direct antimicrobial function from dermal adipocytes during skin infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Abtin, A. et al. Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nat. Immunol. 15, 45–53 (2014).

    CAS  PubMed  Google Scholar 

  36. 36

    Otto, M. Staphylococcus aureus toxins. Curr. Opin. Microbiol. 17, 32–37 (2014).

    CAS  PubMed  Google Scholar 

  37. 37

    Murphy, K. M. Transcriptional control of dendritic cell development. Adv. Immunol. 120, 239–267 (2013).

    CAS  PubMed  Google Scholar 

  38. 38

    Malissen, B., Tamoutounour, S. & Henri, S. The origins and functions of dendritic cells and macrophages in the skin. Nat. Rev. Immunol. 14, 417–428 (2014).

    CAS  PubMed  Google Scholar 

  39. 39

    Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).

    CAS  PubMed  Google Scholar 

  40. 40

    Hoeffel, G. et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J. Exp. Med. 209, 1167–1181 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Haniffa, M., Bigley, V. & Collin, M. Human mononuclear phagocyte system reunited. Semin. Cell Dev. Biol. 41, 59–69 (2015).

    CAS  PubMed  Google Scholar 

  42. 42

    Bedoui, S. et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat. Immunol. 10, 488–495 (2009). This paper shows that CD103+ DCs are the main skin migratory subtype that can cross-present viral and self antigens.

    CAS  PubMed  Google Scholar 

  43. 43

    Haniffa, M. et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity 37, 60–73 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Schlitzer, A. et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38, 970–983 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Vander Lugt, B. et al. Transcriptional programming of dendritic cells for enhanced MHC class II antigen presentation. Nat. Immunol. 15, 161–167 (2014).

    CAS  PubMed  Google Scholar 

  46. 46

    Kolts, R. L., Maki, H. S., Kuehner, M. E., Roberts, R. C. & Sautter, R. D. Enhanced streptokinase-induced thrombolysis using heparin in a rabbit model. J. Invest. Surg. 2, 431–436 (1989).

    CAS  PubMed  Google Scholar 

  47. 47

    Tussiwand, R. et al. Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses. Immunity 42, 916–928 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Briseno, C. G., Murphy, T. L. & Murphy, K. M. Complementary diversification of dendritic cells and innate lymphoid cells. Curr. Opin. Immunol. 29, 69–78 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Scharschmidt, T. C. et al. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity 43, 1011–1021 (2015). This paper describes the characterization of FOXP3+ T reg accumulation in neonate skin and subsequent regulatory function in host–microbiota interaction.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Hansen, S. & Lehr, C. M. Transfollicular delivery takes root: the future for vaccine design? Expert Rev. Vaccines 13, 5–7 (2014).

    CAS  PubMed  Google Scholar 

  51. 51

    Igyarto, B. Z. et al. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses. Immunity 35, 260–272 (2011). This paper reveals specialization of skin-resident DCs during skin infection.

    CAS  PubMed  Google Scholar 

  52. 52

    Kashem, S. W. et al. Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation. Immunity 42, 356–366 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Kobayashi, T. et al. Dysbiosis and Staphylococcus aureus colonization drives inflammation in atopic dermatitis. Immunity 42, 756–766 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Kautz-Neu, K. et al. Langerhans cells are negative regulators of the anti-Leishmania response. J. Exp. Med. 208, 885–891 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Martinez-Lopez, M., Iborra, S., Conde-Garrosa, R. & Sancho, D. Batf3-dependent CD103+ dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice. Eur. J. Immunol. 45, 119–129 (2015).

    CAS  PubMed  Google Scholar 

  56. 56

    Brewig, N. et al. Priming of CD8+ and CD4+ T cells in experimental leishmaniasis is initiated by different dendritic cell subtypes. J. Immunol. 182, 774–783 (2009).

    CAS  PubMed  Google Scholar 

  57. 57

    Ng, L. G. et al. Migratory dermal dendritic cells act as rapid sensors of protozoan parasites. PLoS Pathog. 4, e1000222 (2008).

    PubMed  PubMed Central  Google Scholar 

  58. 58

    Seneschal, J., Clark, R. A., Gehad, A., Baecher-Allan, C. M. & Kupper, T. S. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 36, 873–884 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Akbari, M. et al. IRF4 in dendritic cells inhibits IL-12 production and controls Th1 immune responses against Leishmania major. J. Immunol. 192, 2271–2279 (2014).

    CAS  PubMed  Google Scholar 

  60. 60

    Fabri, M. et al. Vitamin D is required for IFN-γ-mediated antimicrobial activity of human macrophages. Sci. Transl Med. 3, 104ra102 (2011).

    PubMed  PubMed Central  Google Scholar 

  61. 61

    Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157–161 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Kashem, S. W. et al. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity. Immunity 43, 515–526 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Ribeiro-Gomes, F. L., Peters, N. C., Debrabant, A. & Sacks, D. L. Efficient capture of infected neutrophils by dendritic cells in the skin inhibits the early anti-leishmania response. PLoS Pathog. 8, e1002536 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Shen, W. et al. Adaptive immunity to murine skin commensals. Proc. Natl Acad. Sci. USA 111, E2977–E2986 (2014).

    CAS  PubMed  Google Scholar 

  65. 65

    Scholz, F., Badgley, B. D., Sadowsky, M. J. & Kaplan, D. H. Immune mediated shaping of microflora community composition depends on barrier site. PLoS ONE 9, e84019 (2014).

    PubMed  PubMed Central  Google Scholar 

  66. 66

    Battaglia, M. et al. Induction of tolerance in type 1 diabetes via both CD4+CD25+ T regulatory cells and T regulatory type 1 cells. Diabetes 55, 1571–1580 (2006).

    CAS  PubMed  Google Scholar 

  67. 67

    Lehman, H. Skin manifestations of primary immune deficiency. Clin. Rev. Allergy Immunol. 46, 112–119 (2014).

    CAS  PubMed  Google Scholar 

  68. 68

    Rezaei, N., de Vries, E., Gambineri, E. & Haddad, E. in Stiehm's immune deficiencies. Chap. 1 (eds Sullivan, E. K. & Stiehm, E. R.) 3–59 (Academic, 2014).

    Google Scholar 

  69. 69

    Smeekens, S. P. et al. Skin microbiome imbalance in patients with STAT1/STAT3 defects impairs innate host defense responses. J. Innate Immun. 6, 253–262 (2014).

    CAS  PubMed  Google Scholar 

  70. 70

    Kong, H. H. et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 22, 850–859 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    van Rensburg, J. J. et al. The human skin microbiome associates with the outcome of and is influenced by bacterial infection. MBio 6, e01315–01315 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Belkaid, Y., Piccirilo. A. C., Mendez, S., Shevack, E. Sacks, D. L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002). This study is the first demonstration that T reg cells can mediate skin microbial persistence and maintenance of concomitant immunity.

    CAS  PubMed  Google Scholar 

  73. 73

    Suffia, I. J., Reckling, S. K., Piccirillo, C. A., Goldszmid, R. S. & Belkaid, Y. Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. J. Exp. Med. 203, 777–788 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Dudda, J. C., Perdue, N., Bachtanian, E. & Campbell, D. J. Foxp3+ regulatory T cells maintain immune homeostasis in the skin. J. Exp. Med. 205, 1559–1565 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Godfrey, V. L., Wilkinson, J. E. & Russell, L. B. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am. J. Pathol. 138, 1379–1387 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Sanchez Rodriguez, R. et al. Memory regulatory T cells reside in human skin. J. Clin. Invest. 124, 1027–1036 (2014).

    PubMed  PubMed Central  Google Scholar 

  77. 77

    Belkaid, Y. & Tarbell, K. Regulatory T cells in the control of host-microorganism interactions*. Annu. Rev. Immunol. 27, 551–589 (2009).

    CAS  PubMed  Google Scholar 

  78. 78

    Nosbaum, A. et al. Cutting edge: regulatory T cells facilitate cutaneous wound healing. J. Immunol. 196, 2010–2014 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Chiu, I. M. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52–57 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Witherden, D. A., Ramirez, K. & Havran, W. L. Multiple receptor-ligand interactions direct tissue-resident γδ T cell activation. Front. Immunol. 5, 602 (2014).

    PubMed  PubMed Central  Google Scholar 

  81. 81

    Laggner, U. et al. Identification of a novel proinflammatory human skin-homing Vγ9Vδ2 T cell subset with a potential role in psoriasis. J. Immunol. 187, 2783–2793 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Gray, E. E., Suzuki, K. & Cyster, J. G. Cutting edge: identification of a motile IL-17-producing γδ T cell population in the dermis. J. Immunol. 186, 6091–6095 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Sumaria, N. et al. Cutaneous immunosurveillance by self-renewing dermal γδ T cells. J. Exp. Med. 208, 505–518 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Gray, E. E. et al. Deficiency in IL-17-committed Vγ4+ γδ T cells in a spontaneous Sox13-mutant CD45.1+ congenic mouse substrain provides protection from dermatitis. Nat. Immunol. 14, 584–592 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Ramirez-Valle, F., Gray, E. E. & Cyster, J. G. Inflammation induces dermal Vγ4+ γδT17 memory- like cells that travel to distant skin and accelerate secondary IL-17-driven responses. Proc. Natl Acad. Sci. USA 112, 8046–8051 (2015).

    CAS  PubMed  Google Scholar 

  86. 86

    Maher, B. M. et al. Nlrp-3-driven interleukin 17 production by γδT cells controls infection outcomes during Staphylococcus aureus surgical site infection. Infect. Immun. 81, 4478–4489 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Murphy, A. G. et al. Staphylococcus aureus infection of mice expands a population of memory γδ T cells that are protective against subsequent infection. J. Immunol. 192, 3697–3708 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Clark, R. A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 4431–4439 (2006).

    CAS  PubMed  Google Scholar 

  89. 89

    Carbone, F. R. Tissue-resident memory T cells and fixed immune surveillance in nonlymphoid organs. J. Immunol. 195, 17–22 (2015).

    CAS  PubMed  Google Scholar 

  90. 90

    Schenkel, J. M. & Masopust, D. Tissue-resident memory T cells. Immunity 41, 886–897 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).

    CAS  PubMed  Google Scholar 

  92. 92

    Watanabe, R. et al. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci. Transl Med. 7, 279ra39 (2015).

    PubMed  PubMed Central  Google Scholar 

  93. 93

    Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524–530 (2009). This study uncovers for the first time a protective role for T RM cells.

    CAS  PubMed  Google Scholar 

  94. 94

    Mueller, S. N., Gebhardt, T., Carbone, F. R. & Heath, W. R. Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 31, 137–161 (2013).

    CAS  PubMed  Google Scholar 

  95. 95

    Peters, N. C. et al. Chronic parasitic infection maintains high frequencies of short-lived Ly6C+CD4+ effector T cells that are required for protection against re-infection. PLoS Pathog. 10, e1004538 (2014).

    PubMed  PubMed Central  Google Scholar 

  96. 96

    Mackay, L. K. et al. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc. Natl Acad. Sci. USA 109, 7037–7042 (2012).

    CAS  PubMed  Google Scholar 

  97. 97

    Shin, H. & Iwasaki, A. Generating protective immunity against genital herpes. Trends Immunol. 34, 487–494 (2013).

    CAS  PubMed  Google Scholar 

  98. 98

    Owens, P., Han, G., Li, A. G. & Wang, X. J. The role of Smads in skin development. J. Invest. Dermatol. 128, 783–790 (2008).

    CAS  PubMed  Google Scholar 

  99. 99

    Mackay, L. K. et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294–1301 (2013).

    CAS  PubMed  Google Scholar 

  100. 100

    Suffia, I., Reckling, S., Salay, G. & Belkaid, Y. A role for CD103 in Treg retention at site of Leishmania major infection. J. Immunol. 174, 5444–5455 (2005).

    CAS  PubMed  Google Scholar 

  101. 101

    Cyster, J. G. & Schwab, S. R. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu. Rev. Immunol. 30, 69–94 (2012).

    CAS  PubMed  Google Scholar 

  102. 102

    Zaid, A. et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl Acad. Sci. USA 111, 5307–5312 (2014).

    CAS  PubMed  Google Scholar 

  103. 103

    Jiang, X. et al. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 483, 227–231 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).

    CAS  PubMed  Google Scholar 

  105. 105

    Ariotti, S. et al. Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc. Natl Acad. Sci. USA 109, 19739–19744 (2012).

    CAS  PubMed  Google Scholar 

  106. 106

    Zhang, Q. et al. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. J. Exp. Med. 211, 2549–2566 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Knickelbein, J. E. et al. Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 322, 268–271 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Muller, A. J. et al. CD4+ T cells rely on a cytokine gradient to control intracellular pathogens beyond sites of antigen presentation. Immunity 37, 147–157 (2012).

    CAS  PubMed  Google Scholar 

  109. 109

    Schenkel, J. M. et al. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Ariotti, S. et al. T cell memory. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. Science 346, 101–105 (2014). This paper reveals the bystander protective effect of T RM cells on skin immunity.

    CAS  PubMed  Google Scholar 

  111. 111

    Crosby, E. J., Goldschmidt, M. H., Wherry, E. J. & Scott, P. Engagement of NKG2D on bystander memory CD8 T cells promotes increased immunopathology following Leishmania major infection. PLoS Pathog. 10, e1003970 (2014).

    PubMed  PubMed Central  Google Scholar 

  112. 112

    Leyden, J. J., Marples, R. R. & Kligman, A. M. Staphylococcus aureus in the lesions of atopic dermatitis. Br. J. Dermatol. 90, 525–530 (1974).

    CAS  PubMed  Google Scholar 

  113. 113

    Gao, Z., Tseng, C. H., Strober, B. E., Pei, Z. & Blaser, M. J. Substantial alterations of the cutaneous bacterial biota in psoriatic lesions. PLoS ONE 3, e2719 (2008).

    PubMed  PubMed Central  Google Scholar 

  114. 114

    Chalmers, R. J., O'Sullivan, T., Owen, C. M. & Griffiths, C. E. A systematic review of treatments for guttate psoriasis. Br. J. Dermatol. 145, 891–894 (2001).

    CAS  PubMed  Google Scholar 

  115. 115

    Marples, R. R., Heaton, C. L. & Kligman, A. M. Staphylococcus aureus in psoriasis. Arch. Dermatol. 107, 568–570 (1973).

    CAS  PubMed  Google Scholar 

  116. 116

    Nakamura, Y. et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature 503, 397–401 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Niebuhr, M. et al. Staphylococcal α-toxin is a strong inducer of interleukin-17 in humans. Infect. Immun. 79, 1615–1622 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Dastgheyb, S. S. & Otto, M. Staphylococcal adaptation to diverse physiologic niches: an overview of transcriptomic and phenotypic changes in different biological environments. Future Microbiol. 10, 1981–1995 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl Acad. Sci. USA 108, 5354–5359 (2011).

    CAS  PubMed  Google Scholar 

  120. 120

    Grice, E. A. et al. Longitudinal shift in diabetic wound microbiota correlates with prolonged skin defense response. Proc. Natl Acad. Sci. USA 107, 14799–14804 (2010).

    CAS  PubMed  Google Scholar 

  121. 121

    Fitz-Gibbon, S. et al. Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J. Invest. Dermatol. 133, 2152–2160 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Kang, D., Shi, B., Erfe, M. C., Craft, N. & Li, H. Vitamin B12 modulates the transcriptome of the skin microbiota in acne pathogenesis. Sci. Transl Med. 7, 293ra103 (2015).

    PubMed  PubMed Central  Google Scholar 

  123. 123

    Barker, J. N. et al. Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood. J. Investigative Dermatol. 127, 564–567 (2007).

    CAS  Google Scholar 

  124. 124

    Brown, S. J. et al. Prevalent and low-frequency null mutations in the filaggrin gene are associated with early-onset and persistent atopic eczema. J. Investigative Dermatol. 128, 1591–1594 (2008).

    CAS  Google Scholar 

  125. 125

    Natsuga, K., Cipolat, S. & Watt, F. M. Increased bacterial load and expression of antimicrobial peptides in skin of barrier-deficient mice with reduced cancer susceptibility. J. Invest. Dermatol. 136, 99–106 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Di Meglio, P., Villanova, F. & Nestle, F. O. Psoriasis. Cold Spring Harb. Perspect. Med. 4 (2014).

  127. 127

    Hoste, E. et al. Innate sensing of microbial products promotes wound-induced skin cancer. Nat. Commun. 6, 5932 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

  129. 129

    Zeeuwen, P. L. et al. Microbiome dynamics of human epidermis following skin barrier disruption. Genome Biol. 13, R101 (2012).

    PubMed  PubMed Central  Google Scholar 

  130. 130

    Hand, T. & Belkaid, Y. Microbial control of regulatory and effector T cell responses in the gut. Curr. Opin. Immunol. 22, 63–72 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Leung, D. Y., Walsh, P., Giorno, R. & Norris, D. A. A potential role for superantigens in the pathogenesis of psoriasis. J. Invest. Dermatol. 100, 225–228 (1993).

    CAS  PubMed  Google Scholar 

  132. 132

    Reginald, K. et al. Immunoglobulin E antibody reactivity to bacterial antigens in atopic dermatitis patients. Clin. Exp. Allergy 41, 357–369 (2011).

    CAS  PubMed  Google Scholar 

  133. 133

    Sims, J. E. & Smith, D. E. The IL-1 family: regulators of immunity. Nat. Rev. Immunol. 10, 89–102 (2010).

    CAS  PubMed  Google Scholar 

  134. 134

    Donia, M. S. & Fischbach, M. A. Human microbiota. Small molecules from the human microbiota. Science 349, 1254766 (2015).

    PubMed  PubMed Central  Google Scholar 

  135. 135

    Medema, M. H. & Fischbach, M. A. Computational approaches to natural product discovery. Nat. Chem. Biol. 11, 639–648 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Marples, R. R., Downing, D. T. & Kligman, A. M. Control of free fatty acids in human surface lipids by Corynebacterium acnes. J. Invest. Dermatol. 56, 127–131 (1971).

    CAS  PubMed  Google Scholar 

  137. 137

    Findley, K. et al. Topographic diversity of fungal and bacterial communities in human skin. Nature 498, 367–370 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Oh, J. et al. Biogeography and individuality shape function in the human skin metagenome. Nature 514, 59–64 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Conlan, S. et al. Staphylococcus epidermidis pan-genome sequence analysis reveals diversity of skin commensal and hospital infection-associated isolates. Genome Biol. 13, R64 (2012).

    PubMed  PubMed Central  Google Scholar 

  140. 140

    Iwase, T. et al. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature 465, 346–349 (2010).

    CAS  PubMed  Google Scholar 

  141. 141

    Sacks, D. & Noben-Trauth, N. The immunology of susceptibility and resistance to Leishmania major in mice. Nat. Rev. Immunol. 2, 845–858 (2002).

    CAS  PubMed  Google Scholar 

  142. 142

    Krishna, S. & Miller, L. S. Innate and adaptive immune responses against Staphylococcus aureus skin infections. Semin. Immunopathol. 34, 261–280 (2012).

    CAS  PubMed  Google Scholar 

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The authors apologize to their colleagues for not having cited all papers relevant to this expanding field of research (and in particular older literature) because of space constraints and strict editorial limitation for reference number. This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. S. T. was supported by an EMBO fellowship. The authors thank all members of the Belkaid laboratory for discussion and more particularly N. Bouladoux and J. Kehr for their editorial help with the manuscript.

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PowerPoint slides



The relationship between two different species that live in close proximity and benefit from one another.


The relationship between two different species that live in close proximity, in which one species (the parasite) benefits at the expense of the other (the host).


The relationship between two different species, in which one species benefits from the other without affecting it.

Antimicrobial peptides

(AMPs). Molecules that can rapidly kill or inactivate a diverse range of microorganisms, including Gram-negative and Gram-positive bacteria, fungi, viruses and parasites.

Sebaceous glands

Small glands in the skin that secrete an oily matter (sebum) into the hair follicles to lubricate the skin and hair.

Lipoteichoic acid

A major component of the cell wall of Gram-positive bacteria such as Staphylococcus epidermidis.


A filament-associated protein that binds to keratin fibres in epithelial cells and is important for maturation of skin epithelial cells into the corneocytes that form the outermost protective layer of human skin.


Sensory receptors on nerve cells that respond to potentially damaging stimuli by sending signals to the spinal cord and brain.

Concomitant immunity

A paradoxical immune status in which resistance to reinfection coincides with the persistence of the original infection.

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Belkaid, Y., Tamoutounour, S. The influence of skin microorganisms on cutaneous immunity. Nat Rev Immunol 16, 353–366 (2016).

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