Staphylococcus aureus-Specific Tissue-Resident Memory CD4+ T Cells Are Abundant in Healthy Human Skin

Abstract

The skin is an immunocompetent tissue that harbors several kinds of immune cells and a plethora of commensal microbes constituting the skin microbiome. Staphylococcus aureus is a prominent skin pathogen that colonizes a large proportion of the human population. We currently have an incomplete understanding of the correlates of protection against S. aureus infection, however genetic and experimental evidence has shown that CD4+ T cells play a key role in orchestrating a protective anti-S. aureus immune response. A high S. aureus-specific memory CD4+ T cell response has been reported in the blood of healthy subjects. Since T cells are more abundant in the skin than in blood, we hypothesized that S. aureus-specific CD4+ T cells could be present in the skin of healthy individuals. Indeed, we observed proliferation of tissue-resident memory CD4+ T cells and production of IL-17A, IL-22, IFN-γ and TNF-β by cells isolated from abdominal skin explants in response to heat-killed S. aureus. Remarkably, these cytokines were produced also during an ex vivo epicutaneous S. aureus infection of human skin explants. These findings highlight the importance of tissue-resident memory CD4+ T cells present at barrier sites such as the skin, a primary entry site for S. aureus. Further phenotypical and functional characterization of these cells will ultimately aid in the development of novel vaccine strategies against this elusive pathogen.

Staphylococcus aureus specific lung resident memory CD4+ Th1 cells attenuate the severity of influenza virus induced secondary bacterial pneumonia

“…S. aureus reactive CD4 + Trm cells are present in human lung tissue and these cells can reactivate following re-exposure to S. aureus to synthesize TNF, IL-17 and to a lesser degree IFNγ. Our findings are consistent with work by Brown et al, who show that S. aureus specific IFNγ producing CD4 + T cells (Th1) are expanded in humans during an S. aureus bloodstream infection 10 and Hendricks et al 39 , who show that both IFNγ as well as IL-17 producing S. aureus -specific CD4 + Trm are present in the skin of healthy individuals. While we observe a low frequency of S. aureus reactive T cells in human lung tissue, it is estimated that on average, ~3.6% of T-cells (range 0.2%–5.7%) present in human peripheral blood respond to S. aureus extracellular antigens 38 .…”

“…In the present study, we show S. aureus reactive Th1 skewed Trm in the lungs of mice can reduce the severity of S. aureus pneumonia. While a high frequency of S. aureus -reactive memory CD4 + T cell has been reported in the blood 10 , 38 and skin 39 of healthy patients it is unclear whether these cells also reside in the lung or whether they adopt the required Th1 polarity needed for enhanced bacterial clearance. We next set out to develop an assay to measure the frequency and polarity of S. aureus reactive CD4 + Trm cells in human lung tissue.…”

T cell receptor sequencing specifies psoriasis as a systemic and atopic dermatitis as a skin-focused, allergen-driven disease

“…The copyright holder for this preprint this version posted July 19, 2021. ; https://doi.org/10.1101/2021.07.14.21260435 doi: medRxiv preprint allergens mirrored by the individual patients´ IgE sensitization profiles resemble a distinct proportion of the inflammatory skin infiltrate. Further T cell targets are most probably microbial antigens (37)(38)(39) and autoantigens (40). Nevertheless, the technical approach of TCR sequencing circumvents the inherent biases of cultivating skin-derived T cells.…”

“…Taken together, this approach shows that, in AD, clonally expanded T cell clones which react to allergens mirrored by the individual patients´ IgE sensitization profiles resemble a distinct proportion of the inflammatory skin infiltrate. Further T cell targets are most probably microbial antigens [54][55][56] and autoantigens 57 . Nevertheless, the technical approach of TCR sequencing circumvents the inherent biases of cultivating skin-derived T cells.…”

Staphylococcus aureus Vaccine Research and Development: The Past, Present and Future, Including Novel Therapeutic Strategies

“…The cytokine response to S. aureus infection as well as the toxicity of Hla and PVL have previously been investigated using skin explant models, generating physiologically valuable data and a launchpad for future ex vivo analysis ( 132 , 133 ). Recently, the presence of S. aureus -specific tissue-resident CD4 + T cells in the skin of healthy subjects has been shown using abdominal skin explants ( 134 ). The protective efficacy of this frontline adaptive immune response could be harnessed by future vaccination strategies ( 135 ).…”