Targeting Skin-Resident Memory T Cells via Vaccination to Combat Staphylococcus aureus Infections
Authors: Jonah Clegg, Elisabetta Soldaini, Fabio Bagnoli, Rachel M. McLoughlin
Journal: Trends in Immunology (2020)

Mammalian tissue-resident memory T cells are a relatively recently identified population added to the arsenal of adaptive immune cells. These cells are thoroughly being investigated in the study of many tissue-specific diseases.Novel vaccination strategies and biotechnological devices are facilitating the harnessing and sampling of tissue-specific immunity in the skin. In addition, the dynamics of skin-wide immunosurveillance are beginning to be understood.While the importance of T cell immunity during Staphylococcus aureus skin and soft-tissue infections is established, determining the correlates of immunity to develop candidate vaccines remains elusive.Skin-resident memory T cells are a possible missing piece in the immunity puzzle of S. aureus infections. Targeting this population may prove to be significant for the development of a putative successful vaccine against skin and soft tissue S. aureus infections. Tissue-resident memory T cells are important in adaptive immunity against many infections, rendering these cells attractive potential targets in vaccine development. Genetic and experimental evidence highlights the importance of cellular immunity in protection from Staphylococcus aureus skin infections, yet skin-resident memory T cells are, thus far, an untested component of immunity during such infections. Novel methods of generating and sampling vaccine-induced skin memory T cells are paralleled by discoveries of global, skin-wide immunosurveillance. We propose skin-resident memory CD4+ T cells as a potential missing link in the search for correlates of protection during S. aureus infections. A better appreciation of their phenotypes and functions could accelerate the development of preventive vaccines against this highly virulent and antibiotic-resistant pathogen. Tissue-resident memory T cells are important in adaptive immunity against many infections, rendering these cells attractive potential targets in vaccine development. Genetic and experimental evidence highlights the importance of cellular immunity in protection from Staphylococcus aureus skin infections, yet skin-resident memory T cells are, thus far, an untested component of immunity during such infections. Novel methods of generating and sampling vaccine-induced skin memory T cells are paralleled by discoveries of global, skin-wide immunosurveillance. We propose skin-resident memory CD4+ T cells as a potential missing link in the search for correlates of protection during S. aureus infections. A better appreciation of their phenotypes and functions could accelerate the development of preventive vaccines against this highly virulent and antibiotic-resistant pathogen. Infection leads to the clonal expansion (see Glossary) of long-lived memory lymphocytes that mediate adaptive immunity. It was typically understood that these memory cell populations exist in the bloodstream and lymphoid organs in which they constantly recirculate, awaiting reactivation, and with limited entry into peripheral tissues. However, in recent years, numerous studies have showcased the existence and importance of a tissue-resident memory T cell (Trm) population during states of infection, cancer, and homeostasis in mammalian hosts. Trm are identified by their disequilibrium with the circulatory system, which distinguishes them from other characterized memory T cell populations, namely, central memory T cells (Tcm) and effector memory T cells (Tem) (Figure 1). In addition to this functional distinction, Trm have also been transcriptionally defined in mice (Box 1) [1.Kumar B.V. et al.Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites.Cell Rep. 2017; 20: 2921-2934Abstract Full Text Full Text PDF PubMed Google Scholar,2.Fonseca R. et al.Developmental plasticity allows outside-in immune responses by resident memory T cells.Nat. Immunol. 2020; 21: 412-421Crossref PubMed Scopus (54) Google Scholar]. Trm inhabit many (if not all) tissues in the host where they reside, acting as sentinels of the adaptive immune response and rapidly responding to invading pathogens. The protective capabilities of Trm have been demonstrated in murine models of infection with fungal, viral, protozoan, and bacterial species in many peripheral tissues, including the skin (Table 1). As such, Trm may represent an exciting novel vaccine target, particularly against tissue-tropic infections. Recently, novel vaccination strategies have been developed in mice to target Trm towards organs such as the skin, lungs, and vaginal mucosae [3.Hobbs S.J. Nolz J.C. Targeted expansion of tissue-resident CD8+ T cells to boost cellular immunity in the skin.Cell Rep. 2019; 29: 2990-2997Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 4.Shin H. Iwasaki A. A vaccine strategy that protects against genital herpes by establishing local memory T cells.Nature. 2012; 491: 463-467Crossref PubMed Scopus (361) Google Scholar, 5.Gálvez-Cancino F. et al.Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma.Oncoimmunology. 2018; 7e1442163Crossref PubMed Scopus (7) Google Scholar, 6.Haddadi S. et al.Mucosal-pull induction of lung-resident memory CD8 T cells in parenteral TB vaccine-primed hosts requires cognate antigens and CD4 T cells.Front. Immunol. 2019; 10: 2075Crossref PubMed Scopus (5) Google Scholar]. The skin, in addition to being a primary immunological barrier in the human body, also allows unique manipulation due to its external location. In this opinion piece, we describe recent breakthroughs in skin-targeted vaccinology and skin-resident immunity, with the view of applying these advances towards the study of infections initiating in the skin. Specifically, we highlight scenarios of Staphylococcus aureus infection, a major cause of cutaneous and invasive infections for which no vaccine is currently available and to which antibiotics are rapidly becoming ineffective [7.Chambers H.F. DeLeo F.R. Waves of resistance: Staphylococcus aureus in the antibiotic era.Nat. Rev. Microbiol. 2009; 7: 629-641Crossref PubMed Scopus (1428) Google Scholar]. Though the bulk of published research has focused on CD8+ Trm, we give special consideration to CD4+ Trm, as we might expect this subset to be most relevant based on prior research highlighting their role in S. aureus pathologies [8.Montgomery C.P. et al.Protective immunity against recurrent Staphylococcus aureus skin infection requires antibody and interleukin-17A.Infect. Immun. 2014; 82: 2125-2134Crossref PubMed Scopus (75) Google Scholar, 9.Lacey K.A. et al.Clumping factor B is an important virulence factor during Staphylococcus aureus skin infection and a promising vaccine target.PLoS Pathog. 2019; 15e1007713Crossref PubMed Scopus (4) Google Scholar, 10.Chan L.C. et al.Protective immunity in recurrent Staphylococcus aureus infection reflects localized immune signatures and macrophage-conferred memory.Proc. Natl. Acad. Sci. U. S. A. 2018; 115E11111-11119Crossref Scopus (17) Google Scholar, 11.Brown A.F. et al.Memory Th1 cells are protective in invasive Staphylococcus aureus infection.PLoS Pathog. 2015; 11e1005226Crossref PubMed Scopus (90) Google Scholar]. Furthermore, we posit that systemic immunity alone does not address the full scope of S. aureus infections and, given recent vaccinology progress, the time is apt for future research to consider skin-resident memory T cells as a powerful and exploitable arm of adaptive immunity.Box 1Classifying TrmWhile the ultimate identifying property of Trm is their long-term residency in peripheral tissues and concomitant disequilibrium with the circulation, the expression of specific genes and proteins indicative of tissue residency is more commonly used to classify Trm. The relevance of such markers varies between CD4+ and CD8+ Trm and between Trm of different tissues; however, the most universally accepted marker of tissue residency is CD69 [1.Kumar B.V. et al.Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites.Cell Rep. 2017; 20: 2921-2934Abstract Full Text Full Text PDF PubMed Google Scholar]. CD69 is a cell-surface receptor that is rapidly and transiently expressed on all recently activated T cells, functioning to prevent sphingosine-1-phosphate receptor 1 (S1PR1) mediated egress from tissues into the circulation [77.Shiow L.R. et al.CD69 acts downstream of interferon-α/β to inhibit S1P 1 and lymphocyte egress from lymphoid organs.Nature. 2006; 440: 540-544Crossref PubMed Scopus (0) Google Scholar,78.Mackay L.K. et al.Cutting edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention.J. Immunol. 2015; 194: 2059-2063Crossref PubMed Scopus (233) Google Scholar]. Prolonged expression of CD69, accompanied by downregulation of S1pr1 and its associated transcription factor KLF2, is exclusive to Trm residing in peripheral tissues, with these processes working together as tissue-retention mechanisms in mice [1.Kumar B.V. et al.Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites.Cell Rep. 2017; 20: 2921-2934Abstract Full Text Full Text PDF PubMed Google Scholar,54.Skon C.N. et al.Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells.Nat. Immunol. 2013; 14: 1285-1293Crossref PubMed Scopus (366) Google Scholar]. Further cell surface Trm markers include CD103, an integrin that binds to E-cadherin expressed by epithelial cells [79.Karecla P.I. et al.Recognition of E-cadherin on epithelial cells by the mucosal T cell integrin αM290β7 (αEβ7).Eur. J. Immunol. 1995; 25: 852-856Crossref PubMed Scopus (0) Google Scholar]. Its expression, however, is less ubiquitous amongst Trm, especially in CD4+ Trm, with studies reporting highly variable amounts of CD103 on CD69+ CD4+ Trm populations [17.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. 2015; 7279ra39Crossref PubMed Scopus (254) Google Scholar,28.Wilk M.M. et al.Lung CD4 tissue-resident memory T cells mediate adaptive immunity induced by previous infection of mice with Bordetella pertussis.J. Immunol. 2017; 199: 233-243Crossref PubMed Scopus (63) Google Scholar,80.Amezcua Vesely M.C. et al.Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection.Cell. 2019; 178: 1176-1188Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar,81.Xu N. et al.Vaccine-induced gastric CD4+ tissue-resident memory T cells proliferate in situ to amplify immune response against Helicobacter pylori insult.Helicobacter. 2019; 24e12652Crossref PubMed Scopus (2) Google Scholar]. It is possible that CD103 is involved in the anatomical organization of Trm, facilitating their migration towards the epithelial layers of the tissue, such as the epidermis of the skin, binding to E-cadherin expressed by keratinocytes. CD49a is another integrin marker associated with Trm, yet reports indicate that less than 15% of human skin-derived T cells express CD49a, making its putative use as a canonical marker of skin-residency, unwise [82.Purwar R. et al.Resident memory T cells (TRM) are abundant in human lung: diversity, function, and antigen specificity.PLoS One. 2011; 6e16245Crossref PubMed Scopus (0) Google Scholar].Table 1Tissue-Specific Infections with Documented Protective Roles for Tissue-Resident CD4+ and/or CD8+ T Cells in MiceaAbbreviations: HBV, hepatitis B virus; HSV-1, herpes simplex virus-1; HSV-2, herpes simplex virus-2; RSV, respiratory syncytial virus; VV, vaccinia virus.TissueVirusBacteriumFungusParasiteRefsbThe studies referenced here are predominantly based on murine models of infection.SkinHSV-1VVcProtective role for CD8+ Trm.Candida albicansdProtective role for CD4+ Trm.Leishmania majordProtective role for CD4+ Trm.[13.Park C.O. et al.Staged development of long-lived T-cell receptor αβ TH17 resident memory T-cell population to Candida albicans after skin infection.J. Allergy Clin. Immunol. 2018; 142: 647-662Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 14.Glennie N.D. et al.Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection.J. Exp. Med. 2015; 212: 1405-1414Crossref PubMed Google Scholar, 15.Jiang X. et al.Skin infection generates non-migratory memory CD8 + T RM cells providing global skin immunity.Nature. 2012; 483: 227-231Crossref PubMed Scopus (0) Google Scholar, 16.Park S.L. et al.Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses article.Nat. Immunol. 2018; 19: 183-191Crossref PubMed Scopus (0) Google Scholar]Intestinal mucosaSalmonella enterica TyphimuriumdProtective role for CD4+ Trm.Citrobacter rodentiumdProtective role for CD4+ Trm.Listeria monocytogenescProtective role for CD8+ Trm.Heligmosomoides polygyrusdProtective role for CD4+ Trm.[29.Bishu S. et al.Citrobacter rodentium induces tissue-resident memory CD4 T cells.Infect. Immun. 2019; 87e00295Crossref PubMed Scopus (6) Google Scholar,97.Benoun J.M. et al.Optimal protection against Salmonella infection requires noncirculating memory.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: 10416-10421Crossref PubMed Scopus (18) Google Scholar, 98.Sheridan B.S. et al.Oral infection drives a distinct population of intestinal resident memory CD8+ T cells with enhanced protective function.Immunity. 2014; 40: 747-757Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 99.Steinfelder S. et al.Intestinal helminth infection induces highly functional resident memory CD4+ T cells in mice.Eur. J. Immunol. 2017; 47: 353-363Crossref PubMed Scopus (13) Google Scholar]LungsInfluenza viruseProtective role for both populations.RSVcProtective role for CD8+ Trm.Bordetella pertussisdProtective role for CD4+ Trm. Mycobacterium tuberculosiseProtective role for both populations. Streptococcus pneumoniaedProtective role for CD4+ Trm.Klebsiella pneumoniaedProtective role for CD4+ Trm.[6.Haddadi S. et al.Mucosal-pull induction of lung-resident memory CD8 T cells in parenteral TB vaccine-primed hosts requires cognate antigens and CD4 T cells.Front. Immunol. 2019; 10: 2075Crossref PubMed Scopus (5) Google Scholar,12.Teijaro J.R. et al.Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection.J. Immunol. 2011; 187: 5510-5514Crossref PubMed Scopus (355) Google Scholar,28.Wilk M.M. et al.Lung CD4 tissue-resident memory T cells mediate adaptive immunity induced by previous infection of mice with Bordetella pertussis.J. Immunol. 2017; 199: 233-243Crossref PubMed Scopus (63) Google Scholar,32.Shenoy A.T. et al.Lung CD4+ resident memory T cells remodel epithelial responses to accelerate neutrophil recruitment during pneumonia.Mucosal Immunol. 2020; 13: 334-343Crossref PubMed Scopus (2) Google Scholar,80.Amezcua Vesely M.C. et al.Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection.Cell. 2019; 178: 1176-1188Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar,100.Zens K.D. et al.Vaccine-generated lung tissue–resident memory T cells provide heterosubtypic protection to influenza infection.JCI Insight. 2019; 1e85832Google Scholar, 101.Kinnear E. et al.Airway T cells protect against RSV infection in the absence of antibody.Mucosal Immunol. 2018; 11: 249-256Crossref PubMed Scopus (0) Google Scholar, 102.Perdomo C. et al.Mucosal BCG vaccination induces protective lung-resident memory T cell populations against tuberculosis.MBio. 2016; 7e01686-16Crossref PubMed Scopus (113) Google Scholar]Reproductive tractHSV-2cProtective role for CD8+ Trm.Chlamydia trachomatisdProtective role for CD4+ Trm.[4.Shin H. Iwasaki A. A vaccine strategy that protects against genital herpes by establishing local memory T cells.Nature. 2012; 491: 463-467Crossref PubMed Scopus (361) Google Scholar,103.Stary G. et al.A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells.Science. 2015; 348aaa8205Crossref PubMed Scopus (197) Google Scholar]LiverHBVcProtective role for CD8+ Trm.Plasmodium falciparumdProtective role for CD4+ Trm.[104.Pallett L.J. et al.IL-2 High tissue-resident T cells in the human liver: sentinels for hepatotropic infection.J. Exp. Med. 2017; 214: 1567-1580Crossref PubMed Scopus (0) Google Scholar,105.Tse S.W. et al.Unique transcriptional profile of liver-resident memory CD8+ T cells induced by immunization with malaria sporozoites.Genes Immun. 2013; 14: 302-309Crossref PubMed Scopus (47) Google Scholar]a Abbreviations: HBV, hepatitis B virus; HSV-1, herpes simplex virus-1; HSV-2, herpes simplex virus-2; RSV, respiratory syncytial virus; VV, vaccinia virus.b The studies referenced here are predominantly based on murine models of infection.c Protective role for CD8+ Trm.d Protective role for CD4+ Trm.e Protective role for both populations. Open table in a new tab While the ultimate identifying property of Trm is their long-term residency in peripheral tissues and concomitant disequilibrium with the circulation, the expression of specific genes and proteins indicative of tissue residency is more commonly used to classify Trm. The relevance of such markers varies between CD4+ and CD8+ Trm and between Trm of different tissues; however, the most universally accepted marker of tissue residency is CD69 [1.Kumar B.V. et al.Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites.Cell Rep. 2017; 20: 2921-2934Abstract Full Text Full Text PDF PubMed Google Scholar]. CD69 is a cell-surface receptor that is rapidly and transiently expressed on all recently activated T cells, functioning to prevent sphingosine-1-phosphate receptor 1 (S1PR1) mediated egress from tissues into the circulation [77.Shiow L.R. et al.CD69 acts downstream of interferon-α/β to inhibit S1P 1 and lymphocyte egress from lymphoid organs.Nature. 2006; 440: 540-544Crossref PubMed Scopus (0) Google Scholar,78.Mackay L.K. et al.Cutting edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention.J. Immunol. 2015; 194: 2059-2063Crossref PubMed Scopus (233) Google Scholar]. Prolonged expression of CD69, accompanied by downregulation of S1pr1 and its associated transcription factor KLF2, is exclusive to Trm residing in peripheral tissues, with these processes working together as tissue-retention mechanisms in mice [1.Kumar B.V. et al.Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites.Cell Rep. 2017; 20: 2921-2934Abstract Full Text Full Text PDF PubMed Google Scholar,54.Skon C.N. et al.Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells.Nat. Immunol. 2013; 14: 1285-1293Crossref PubMed Scopus (366) Google Scholar]. Further cell surface Trm markers include CD103, an integrin that binds to E-cadherin expressed by epithelial cells [79.Karecla P.I. et al.Recognition of E-cadherin on epithelial cells by the mucosal T cell integrin αM290β7 (αEβ7).Eur. J. Immunol. 1995; 25: 852-856Crossref PubMed Scopus (0) Google Scholar]. Its expression, however, is less ubiquitous amongst Trm, especially in CD4+ Trm, with studies reporting highly variable amounts of CD103 on CD69+ CD4+ Trm populations [17.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. 2015; 7279ra39Crossref PubMed Scopus (254) Google Scholar,28.Wilk M.M. et al.Lung CD4 tissue-resident memory T cells mediate adaptive immunity induced by previous infection of mice with Bordetella pertussis.J. Immunol. 2017; 199: 233-243Crossref PubMed Scopus (63) Google Scholar,80.Amezcua Vesely M.C. et al.Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection.Cell. 2019; 178: 1176-1188Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar,81.Xu N. et al.Vaccine-induced gastric CD4+ tissue-resident memory T cells proliferate in situ to amplify immune response against Helicobacter pylori insult.Helicobacter. 2019; 24e12652Crossref PubMed Scopus (2) Google Scholar]. It is possible that CD103 is involved in the anatomical organization of Trm, facilitating their migration towards the epithelial layers of the tissue, such as the epidermis of the skin, binding to E-cadherin expressed by keratinocytes. CD49a is another integrin marker associated with Trm, yet reports indicate that less than 15% of human skin-derived T cells express CD49a, making its putative use as a canonical marker of skin-residency, unwise [82.Purwar R. et al.Resident memory T cells (TRM) are abundant in human lung: diversity, function, and antigen specificity.PLoS One. 2011; 6e16245Crossref PubMed Scopus (0) Google Scholar]. Original studies almost a decade ago first showed the existence and protective capabilities of CD4+ Trm in the lungs during murine influenza virus infection [12.Teijaro J.R. et al.Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection.J. Immunol. 2011; 187: 5510-5514Crossref PubMed Scopus (355) Google Scholar]; since then, multiple studies have showcased the key role played by skin-resident memory T cells in the adaptive response to cutaneous infections. For example, after initial challenge with Candida albicans, mice develop pathogen-specific CD4+ Trm in the skin, displaying strong immunogenic activity during ex vivo antigen-specific stimulation [13.Park C.O. et al.Staged development of long-lived T-cell receptor αβ TH17 resident memory T-cell population to Candida albicans after skin infection.J. Allergy Clin. Immunol. 2018; 142: 647-662Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. Following parabiosis with naïve mice, protective immunity is significantly enhanced in infection-experienced mice relative to uninfected parabionts, confirming the tissue-resident nature of this protection [13.Park C.O. et al.Staged development of long-lived T-cell receptor αβ TH17 resident memory T-cell population to Candida albicans after skin infection.J. Allergy Clin. Immunol. 2018; 142: 647-662Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. A similar effect was demonstrated during infection with Leishmania major, whereby skin grafts containing infection-induced CD4+ Trm were shown to drive enhanced recruitment of circulating T cells, conferring optimal immunity to mice during reinfection [14.Glennie N.D. et al.Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection.J. Exp. Med. 2015; 212: 1405-1414Crossref PubMed Google Scholar]. In addition, numerous studies using murine models have revealed CD8+ Trm as stand-alone mediators of adaptive immunity during recurrent skin infections with viral pathogens, such as herpes simplex virus type 1 (HSV-1) and vaccinia virus (VV), following depletion of circulating memory lymphocyte populations [3.Hobbs S.J. Nolz J.C. Targeted expansion of tissue-resident CD8+ T cells to boost cellular immunity in the skin.Cell Rep. 2019; 29: 2990-2997Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,15.Jiang X. et al.Skin infection generates non-migratory memory CD8 + T RM cells providing global skin immunity.Nature. 2012; 483: 227-231Crossref PubMed Scopus (0) Google Scholar,16.Park S.L. et al.Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses article.Nat. Immunol. 2018; 19: 183-191Crossref PubMed Scopus (0) Google Scholar]. The immunogenic activity of Trm has also been exemplified in T cells isolated from human skin: upon isolation and nonspecific activation, CD3+ CD69+ Trm (non-recirculating) express greater amounts of proinflammatory cytokines than CD3+ CD69– memory T cells; the latter previously identified as recirculating (the addition of an anti-CD52 antibody that selectively labeled recirculating cells only) [17.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. 2015; 7279ra39Crossref PubMed Scopus (254) Google Scholar]. Combined, this evidence has implicated tissue-resident T cells as emerging candidate vaccine targets for skin infections. S. aureus is the most frequent causative agent of skin and soft tissue infections (SSTIs), a term encompassing a range of community-acquired (CA) superficial infections, as well as hospital-acquired surgical site infections (SSIs) [18.Ray G.T. et al.Incidence, microbiology, and patient characteristics of skin and soft-tissue infections in a U.S. population: a retrospective population-based study.BMC Infect. Dis. 2013; 13: 252Crossref PubMed Scopus (140) Google Scholar, 19.Talan D.A. et al.Comparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008.Clin. Infect. Dis. 2011; 53: 144-149Crossref PubMed Scopus (229) Google Scholar, 20.Moran G.J. et al.Methicillin-resistant S. aureus infections among patients in the emergency department.N. Engl. J. Med. 2006; 355: 666-674Crossref PubMed Scopus (1874) Google Scholar, 21.Zarb P. et al.The European Centre for Disease Prevention and Control (ECDC) pilot point prevalence survey of healthcare-associated infections and antimicrobial use.Eurosurveillance. 2012; 17: 1-16Crossref Scopus (269) Google Scholar]. In the USA, S. aureus CA-SSTIs are estimated to cost $4.5 billion annually, causing significant strain on health services while also risking the progression into more life-threatening, invasive disease, as seen with staphylococcal bloodstream infections [22.Suaya J.A. et al.Incidence and cost of hospitalizations associated with Staphylococcus aureus skin and soft tissue infections in the United States from 2001 through 2009.BMC Infect. Dis. 2014; 14: 296Crossref PubMed Scopus (83) Google Scholar,23.Tattevin P. et al.Concurrent epidemics of skin and soft tissue infection and bloodstream infection due to community-associated methicillin-resistant Staphylococcus aureus.Clin. Infect. Dis. 2012; 55: 781-788Crossref PubMed Scopus (43) Google Scholar]. In addition, European hospitals have reported that 16–21% of SSIs are caused by S. aureus, leading to a total of 16 000 deaths per year throughout the EU alone, while further affecting regions of the developing world to a disproportionately greater extent [21.Zarb P. et al.The European Centre for Disease Prevention and Control (ECDC) pilot point prevalence survey of healthcare-associated infections and antimicrobial use.Eurosurveillance. 2012; 17: 1-16Crossref Scopus (269) Google Scholar,24.Cassini A. et al.Burden of six healthcare-associated infections on European population health: estimating incidence-based disability-adjusted life years through a population prevalence-based modelling study.PLoS Med. 2016; 13e1002150Crossref PubMed Scopus (204) Google Scholar, 25.European Centre for Disease Prevention and Control Annual Epidemiological Report 2016- Surgical Site Infections. ECDC, 2016Google Scholar, 26.Curcio D. et al.Surgical site infection in elective clean and clean-contaminated surgeries in developing countries.Int. J. Infect. Dis. 2019; 80: 34-45Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. Combined with the ever-growing threat of antimicrobial resistance, a vaccine preventing S. aureus infections is greatly needed. Elucidating the correlates of protective immunity to S. aureus infections is an area of ongoing research that is integral to the development of a candidate vaccine, a task complicated by the fact that S. aureus is also a common human commensal (Box 2). While an important role for neutralizing antibodies is appreciated, the requirement for T cell immunity has become increasingly clear in recent years, particularly during S. aureus SSTIs (Box 3) [27.Miller L.S. et al.Development of a vaccine against Staphylococcus aureus invasive infections: evidence based on human immunity, genetics and bacterial evasion mechanisms.FEMS Microbiol. Rev. 2019; 44: 123-153Crossref Scopus (16) Google Scholar]. Resident T cell responses during S. aureus SSTI however, have yet to be investigated.Box 2Staphylococcal–Skin InteractionsStaphylococcus aureus is a common human commensal. Approximately 20% of individuals are colonized in the nasal mucosa and between 8 and 20% are colonized in the skin at any given time [73.Albrecht V.S. et al.Staphylococcus aureus colonization and strain type at various body sites among patients with a closed abscess and uninfected controls at U.S. emergency departments.J. Clin. Microbiol. 2015; 53: 3478-3484Crossref PubMed Scopus (0) Google Scholar,83.Eriksen N.H.R. et al.Carriage of Staphylococcus aureus among 104 healthy persons during a 19-month period.Epidemiol. Infect. 1995; 115: 51-60Crossref PubMed Google Scholar,84.Young B.C. et al.Multi-site and nasal swabbing for carriage of Staphylococcus aureus: what does a single nose swab predict?.J. Hosp. Infect. 2017; 96: 232-237Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. Such nonpathologic colonization is strongly suggestive of context-dependent outcomes related to the presence of S. aureus on human skin. Indeed, while much study of S. aureus has focused on the inflammatory response to infection, less is known about the immune response t