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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.

CD1a is predominantly expressed by antigen-presenting cells in the skin, where it modulates immune responses through lipid antigen presentation to T cells. Increasing evidence supports a role of regulatory T cells (Tregs) in the control of skin immune programs. However, whether Tregs can recognise CD1a and maintain immune homeostasis remains unstudied. The first aim of this study was to interrogate the functional interaction of Tregs with CD1a and characterise CD1a-reactive Tregs in health and psoriasis. Here, a subpopulation of polyclonal Tregs (~2%) was found to secrete the immunosuppressive cytokine IL-10, but not skin inflammation-associated cytokines, in a CD1a-dependent manner. Moreover, CD1a-reactive Tregs were demonstrated to functionally interact with CD1a presenting skin relevant lipids. Ex vivo single cell sequencing of CD1a-reactive Tregs further revealed that upon CD1a stimulation, CD1a-reactive IL-10-secreting effector/memory Tregs from healthy controls and psoriasis patients downregulate Treg lineage and phenotype markers and shift towards a central/memory phenotype. Moreover, gene expression analysis suggests that CD1a-reactive Tregs may present a subpopulation with impaired suppressive capacity. The second aim of this study was to investigate the therapeutic potential of butyrate and related fatty acids (FAs) to modulate CD1a-reactive T cell activation via alteration of CD1a expression. Here, butyrate and related FAs were demonstrated to partially inhibit expression of group 1 CD1 molecules on monocyte-derived dendritic cells (moDCs) while not affecting general moDC differentiation. CD1a-mediated T cell responses by moDCs were unchanged on treatment with butyrate and related FAs, suggesting that these compounds cannot modulate CD1a expression sufficiently to influence CD1a-mediated T cell responses. The findings presented in this study demonstrate that Tregs can functionally interact with CD1a and undergo transcriptional and phenotypic re-programming upon CD1a engagement, which in turn may influence skin immunity. While partial modulation of CD1a expression may not be sufficient to alter CD1a-mediated T cell activation, the modulation of CD1a-mediated Treg responses may present a novel therapeutic target for the treatment of skin inflammatory disease.

There is very limited information available on child and adolescent psychiatry (CAP) training in the Southeast European (SEE) region. The objective of this study was to fill in this gap by presenting descriptive data on CAP training and national mental health services for children and adolescent in 11 SEE countries. On the initiative of World Psychiatric Association—CAP section, national CAP association boards from each SEE country allocated one member to the Consortium on Academic Child and Adolescent Psychiatry in SEE (CACAP SEE) in 2018. Using an internally distributed questionnaire, CACAP SEE members provided information on the CAP training structure and mental health care. Ten out of eleven SEE countries recognized CAP as a separate specialty. Duration of training did not differ much between the SEE countries. Other components were more variable (availability of rotations, overseas electives, and inclusion of psychotherapy). Ten countries were familiar with the CAP requirements of the European Union of Medical Specialists (UEMS–CAP) and five provided the training in accordance with it. Nine countries had less than 36 board-certified child and adolescent psychiatrists practicing in the country. The number of general psychiatrists treating children and adolescents with mental disorders was higher than the number of CAP specialists in five of the countries. Although CAP was recognized as a separate specialty in the vast majority of SEE countries, there was a substantial variation among them in available CAP training. In most of the countries, there is a considerable lack of CAP specialists for several reasons, including loss of trained specialists to other countries. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.