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

Abstract

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.

CD1a and skin T cells: a pathway for therapeutic intervention

“…Recently, it was shown that activated GAS-responsive CD1a-reactive T cells were enriched in patients with psoriasis and were predominantly of the type 17 subtype, with a proportion of these being responsive to lysophosphatidylcholine, which is a known permissive endogenous CD1a ligand. 35 Experiments performed using TCR-transgenic T cells generated via homology-directed repair confirmed these GAS-specific CD1a-reactive T-cell responses to be TCR dependent. As mice do not express CD1a, Chen et al utilized a humanized CD1a-transgenic (hCD1a-Tg) mouse model to demonstrate the characteristic histological features of psoriasis (hyperplasia of the epidermis and dermis with pronounced rete ridges) induced by the presence of GAS.…”

“…Between 5% and 10% of cutaneous T cells are CD1a-reactive. 35 In addition, CD1a-reactive T cells are found within peripheral blood and can be recruited into the skin through cutaneous homing receptors such as CLA, CCR4, CCR6 and CCR10. 36 Interestingly, unlike conventional MHC-restricted T cells, CD1a-reactive T-cell responses do not appear to always be limited to specific CD1a-lipid combinations resulting in the potential for different lipid antigens to serve as universal CD1a ligands.…”

“… 39 Moreover, CD1a-reactive T cells can produce a diverse panel of cytokines and can contribute to cutaneous inflammation under certain circumstances. 10 , 14 , 35 , 37 , 40–44 CD1a-reactive T cells are thought to largely express an αβ TCR, but subsets can express a γδ TCR. 45 In addition, they may express either a CD4 or CD8 co-receptor.…”

“…As mice do not express CD1a, Chen et al utilized a humanized CD1a-transgenic (hCD1a-Tg) mouse model to demonstrate the characteristic histological features of psoriasis (hyperplasia of the epidermis and dermis with pronounced rete ridges) induced by the presence of GAS. 35 …”

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

“…In more recent work, the interplay of bacteria‐responsive CD1a‐reactive T cells and autoreactivity was investigated in the setting of psoriasis, where Streptococcal infection could promote the generation of polyfunctional CD1a‐autoreactive T cells that produce type 1, 2, and 17 cytokines [26]. The data are consistent with earlier work showing that individuals with psoriasis have elevated frequencies of CD1a‐autoreactive and cytokine‐producing T cells in the blood and skin, explained at least in part through the activity of endogenous phospholipase A2 [22–24].…”