Staphylococcal phosphatidylglycerol antigens activate human T cells via CD1a

Monnot, Gwennaëlle; Wegrecki, Marcin; Cheng, Tan-Yun; Chen, Yi‐Ling; Sallee, B.; Chakravarthy, Reka; Karantza, Ioanna Maria; Tin, Shin Yi; Khaleel, Alexandra E.; Monga, Isha; Uwakwe, Laura N; Tillman, Alice; Cheng, Bin; Youssef, Soundos; Ng, Soo Weei; Shahine, Adam; García-Vilas, Javier A.; Uhlemann, Anne‐Catrin; Bordone, Lindsey; Han, Arnold; Rohde, Christine; Ogg, Graham S.; Moody, D. Branch; Rossjohn, Jamie; Jong, Annemieke de

doi:10.1038/s41590-022-01375-z

Cited by 19 publications

(19 citation statements)

References 63 publications

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“…Importantly, we show that the expression of the HIV co-receptor CCR5 [18,28], well established to be increased upon cell activation [28,29], was not impacted by drug dose. This was similarly the finding with CD1a + cells in the foreskin showing that epithelial dendritic cells [21,30] and/or epidermal Langerhans cells [23] were consistently present across the different trial arms but unchanged in numbers. In contrast to studies using topical PrEP whereby 1% tenofovir gel increased T-cell densities in rectal tissue [11] and CD4 + T-cell activation in endocervical tissue [13], we show in our study that oral PrEP dosing has no effect on local foreskin T-cell immunity.…”

Section: Discussionsupporting

confidence: 81%

A randomized clinical trial of on-demand oral pre-exposure prophylaxis does not modulate lymphoid/myeloid HIV target cell density in the foreskin

Rametse,

Webb,

Herrera

et al. 2023

Aids

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a,d , for the CHAPS consortium Objectives: As topical pre-exposure prophylaxis (PrEP) has been shown to cause immune modulation in rectal or cervical tissue, our aim was to examine the impact of oral PrEP on lymphoid and myeloid changes in the foreskin in response to dosing and timing of drug administration.Design: HIV-negative male individuals (n ¼ 144) were recruited in South Africa and Uganda into an open-label randomized controlled trial in a 1

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Section: Discussionsupporting

confidence: 81%

A randomized clinical trial of on-demand oral pre-exposure prophylaxis does not modulate lymphoid/myeloid HIV target cell density in the foreskin

Rametse,

Webb,

Herrera

et al. 2023

Aids

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“…Recent advances in CD1a tetramer technology facilitate the identification of CD1a-reactive T cells recognizing specific lipids ( 36 , 67 ). To detect the frequency of CD1a-LPC–reactive T cells in individuals with plaque psoriasis, we next tetramerized CD1a monomers treated with CHAPS detergent (mock) or different species of LPCs (fig.…”

Section: Resultsmentioning

confidence: 99%

“…Biotinylated human CD1a monomers (NIH Tetramer Core Facility) were produced in human embryonic kidney 293–derived cell lines ( 36 , 67 ). CD1a (10 μg) was treated with a 100X molar excess of LPC 18:1 or LPC 18:0 (Avanti Polar Lipids) in tris-buffered saline containing 0.25% CHAPS or vehicle alone (mock) for 16 hours at 37°C and tetramerized with PE-streptavidin (High Concentration; BioLegend) at a molar ratio of 5:1.…”

Section: Methodsmentioning

confidence: 99%

“…T cell recognition of permissive skin lipid antigens can be mediated, at least in some cases, through T cell receptor (TCR) engagement of the A′ roof of CD1a without direct lipid:TCR contact, helping to explain broad lipid reactivity ( 33 , 34 ). CD1a-reactive T cells have been shown to respond to mycobacterial and staphylococcal antigens, implicating a role in bacterial defense ( 24 , 28 , 35 , 36 ). However, there are no studies that have investigated the role of CD1a reactivity in the immune response to GAS and the consequences for associated inflammatory disease.…”

Section: Introductionmentioning

confidence: 99%

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Group A Streptococcus induces CD1a-autoreactive T cells and promotes psoriatic inflammation

Chen

Babu

et al. 2023

Sci. Immunol.

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Group A Streptococcus (GAS) infection is associated with multiple clinical sequelae, including different subtypes of psoriasis. Such post-streptococcal disorders have been long known but are largely unexplained. CD1a is expressed at constitutively high levels by Langerhans cells and presents lipid antigens to T cells, but the potential relevance to GAS infection has not been studied. Here, we investigated whether GAS-responsive CD1a-restricted T cells contribute to the pathogenesis of psoriasis. Healthy individuals had high frequencies of circulating and cutaneous GAS-responsive CD4 + and CD8 + T cells with rapid effector functions, including the production of interleukin-22 (IL-22). Human skin and blood single-cell CITE-seq analyses of IL-22–producing T cells showed a type 17 signature with proliferative potential, whereas IFN-γ–producing T cells displayed cytotoxic T lymphocyte characteristics. Furthermore, individuals with psoriasis had significantly higher frequencies of circulating GAS-reactive T cells, enriched for markers of activation, cytolytic potential, and tissue association. In addition to responding to GAS, subsets of expanded GAS-reactive T cell clones/lines were found to be autoreactive, which included the recognition of the self-lipid antigen lysophosphatidylcholine. CD8 + T cell clones/lines produced cytolytic mediators and lysed infected CD1a-expressing cells. Furthermore, we established cutaneous models of GAS infection in a humanized CD1a transgenic mouse model and identified enhanced and prolonged local and systemic inflammation, with resolution through a psoriasis-like phenotype. Together, these findings link GAS infection to the CD1a pathway and show that GAS infection promotes the proliferation and activation of CD1a-autoreactive T cells, with relevance to post-streptococcal disease, including the pathogenesis and treatment of psoriasis.

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“…CD1a proteins normally present lipid antigens, and CD1a can be directly recognized by TCRs [2, 3]. These data raise new questions about whether skin‐ resident T cells respond to CD1a itself [3], clinically relevant skin microbiome lipids [4], CD1a‐presented contact allergens [5], or all of the above. In this new view, both MHC and CD1a, presenting either peptides or lipids, can drive physiological and skin disease‐related T‐cell responses.…”

Section: Skin‐resident Memory T Cells In Humansmentioning

confidence: 99%

CD1a and bound lipids drive T‐cell responses in human skin disease

et al. 2023

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In addition to serving as the main physical barrier with the outside world, human skin is abundantly infiltrated with resident αβ T cells that respond differently to self, infectious, microbiome and noxious stimuli. To study skin T cells during infection and inflammation, experimental biologists track T cell surface phenotypes and effector functions, which are often interpreted with the untested assumption that MHC proteins and peptide antigens drive measured responses. However, a broader perspective is that CD1 proteins also activate human T cells, and in skin, Langerhans cells (LC) are abundant antigen presenting cells that express extremely high levels of CD1a. The emergence of new experimental tools, including CD1a tetramers carrying endogenous lipids, now show that CD1a‐reactive T cells comprise a large population of resident T cells in human skin. Here we review studies showing that skin‐derived αβ T cells directly recognize CD1a proteins, and certain bound lipids, such as contact dermatitis allergens, trigger T cell responses. Other natural skin lipids inhibit CD1a‐mediated T cell responses, providing an entry point for the development of therapeutic lipids that block T cell responses. Increasing evidence points to a distinct role of CD1a in type 2 and 22 T cell responses, providing new insights into psoriasis, contact dermatitis and other T cell‐mediated skin diseases.This article is protected by copyright. All rights reserved

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Staphylococcal phosphatidylglycerol antigens activate human T cells via CD1a

Cited by 19 publications

References 63 publications

A randomized clinical trial of on-demand oral pre-exposure prophylaxis does not modulate lymphoid/myeloid HIV target cell density in the foreskin

A randomized clinical trial of on-demand oral pre-exposure prophylaxis does not modulate lymphoid/myeloid HIV target cell density in the foreskin

Group A Streptococcus induces CD1a-autoreactive T cells and promotes psoriatic inflammation

CD1a and bound lipids drive T‐cell responses in human skin disease

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