Molecular Medicine in Paediatrics | Daniela Finke

The outcome of ILC3-T cell interactions is strongly influenced by the tissue microenvironment. In the gut under steady-state conditions, ILC3 subsets express MHCII but lack co-stimulatory molecules, thereby limiting T cell responses to dietary and commensal antigens and promoting tolerance. By contrast, splenic ILC3s promote T cell proliferation and support B cell responses. Comparative phenotypic, transcriptional, and functional analyses demonstrate that ILC3s from the spleen and small intestine display fundamentally distinct molecular and functional profiles. In the gut, microbial signals and cytokines such as IL-23 suppress the antigen-presenting capacity of ILC3s through mTORC1 and STAT3 pathways. These findings highlight the importance of tissue-specific regulation of ILC3 function in balancing immune activation and tolerance within the gut mucosa.

• Lehmann FM et al., 2020. Microbiota-induced signals regulate ILC3-mediated antigen presentation. Nature communications, 11, doi: 10.1038/s41467-020-15612-2.
• Von Burg N et al., 2014. Activated group 3 innate lymphoid cells promote T-cell-mediated immune responses. PNAS, 111(35): 12835-40.

ILC subsets express distinct surface receptors that mediate cell-cell recognition, including receptors classically associated with natural killer (NK) cell function. One such receptor, tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) belongs to the TNF superfamily and enables anti-tumour activity. TRAIL is predominantly expressed by NK and type 1 ILCs (ILC1s). We identified a point mutation in the Ncr1 locus that markedly reduces surface TRAIL expression and impairs the ability of ILC1s to kill TRAIL receptor-expressing target cells. These findings demonstrate that NKp46 regulates the anti-tumour activity of ILC1s by controlling TRAIL expression.

ILC3s, in contrast, are tissue-resident lymphocytes essential for maintaining intestinal barrier immunity and coordinating early responses to bacterial infection. Using novel reporter and cell-labelling strategies, we are now investigating the spatial dynamics and cellular partners of naïve and activated ILC3s across lymphoid and non-lymphoid tissue. Our goal is to delineate the regulatory networks governing ILC3 function during infection and tissue repair and to define their contribution to memory immune cell responses.

• Turchinovich G et al., 2018. NKp46 calibrates tumoricidal potential of type 1 innate lymphocytes by regulating TRAIL expression. J. Immunol. 200, 3762-3768.
• Scandella, E. et al., 2008. Restoration of lymphoid organ integrity through interaction of lymphoid tissue-inducer cells with stroma of the T cell zone. Nature Immunology, 9, 667-675.

We investigate pathways regulating the transition from protective to proinflammatory ILCs, which drive chronic inflammation and contribute to inflammatory bowel disease. We identified mTOR signalling as a key regulator of proinflammatory interferon (IFN)γ release by ILC3s and neutrophil recruitment during colitis. Together, the Finke lab uncovered transcriptional and metabolic control of ILC plasticity, linking mTOR-dependent IFNγ production to ILC-mediated colitis.

• Teufel C et al., 2021. mTOR signalling mediates ILC3-driven immunopathology. Mucosal Immunology, 14(6):1323-1334
• Brasseit J et al., 2015. CD4 T cells are required for both development and maintenance of disease in a new mouse model of reversible colitis. Mucosal Immunology, 9, 689-701.
• Vonarbourg C et al., 2010. Regulated expression of nuclear receptor RORgt confers distinct functional fates to NK cell receptor-expressing RORgt(+) innate lymphocytes. Immunity. 24;33(5):736-51.

Genetically engineered immune cells are critical for advancing preclinical immunotherapy. We established a robust system to immortalize and genetically modify hematopoietic bone marrow (BM) progenitor cells using the fusion protein NUP98Hoxa10HD (NUPA10hd) delivered via viral vectors. This system outperforms conventional transduction methods, as NUPA10hd-immortalized progenitors efficiently generate both myeloid and lymphoid lineages. It enables long-term in vivo studies of migration, differentiation, and cell-cell interactions. We are now applying this approach to dissect the spatial and temporal dynamics of CD4⁺ T cells interacting with dendritic cells or ILC3s in situ.

• Samson GPB, Anslinger N, Legler DF, Finke D. 2025. NUPA10hd-immortalized and genetically engineered progenitors allow studying dendritic cell immune functions. Front. Immunol., 16: 1658429