Antifungal T-cell responses of neonates, infants, and children

• Applicant: Professorin Dr. Monika Christine Brunner-Weinzierl
• Subject Area: Pediatric and Adolescent Medicine ; Immunology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418169051

Adaptive immune responses of neonates, infants and children react differently than those of adults. Others and we were able to show that in fact CD4 + T cell activation and differentiation is highly age-dependent in early life stages. However, this has so far been demonstrated mainly by antigen-nonspecific polyclonal stimulation. New preliminary results now show that even antigen-specific responses - as a model, antifungal T cell responses to peptides and lysates of the fungi Candida albicans or Aspergillus fumigatus - are vigorously initiated from birth. The neonatologically responsive T cell pool consists of 20 different TCR Vβ families, while pediatric and adult pools show dramatically less variability. We could not show an age-dependent bias for IL-4 expression, but a pronounced IL-17 and IL-10 production. Remarkably, only neonatal and infant T cells showed immediate co-expression of multiple cytokines. In addition, only their naive, activated T cells co-express the transcription factors T-bet and RORγt and subsequently their target genes IL-17 and IFNγ. This indicates that neonatal and infant T cells are predetermined to respond rapidly to high fungal plasticity, which may provide a point of intervention for therapeutic interventions.In the present project, we will focus on functional and molecular aspects of age-related antigen-specific T cell activation and differentiation, using as model our well-characterized antifungal responses to Candida albicans and Aspergillus fumigatus in human T cells. First, we will extend our original work on polyclonal, antigen-unspecific T cell activation to antigen-specific, using MELC technology to analyze the T cell APC synapse. Next, we will identify neonatal-type IL-17 production and its plasticity using kinom profiling, for cytokine signalling, stat analysis, and T-cell differentiation approaches. Another goal is the functional and molecular analysis of antifungal IL-10 producers in neonates, infants, and children, which we see as a key switch to shut down T cell responses (including Th17). Differentiation tests, suppression tests and B-cell helper assays are to be carried out for this purpose. In addition, we will identify signalling pathways that will be initiated for the induction of IL-10 expression in neonatal and pediatric T cells.Together, these experiments provide a comprehensive picture of an antigen-specific T cell response of neonates, infants and children and their signalling pathways in CD4+ T cells. In addition, it will provide insights into the hitherto not understood cellular or molecular causes and age-related differences in fungal infections in humans.

• DFG Programme: Research Grants