Features of innate lymphoid cells in human fetal tissues and adult respiratory infection

NK cells and ILC3s are the first lymphoid cells to develop in the human fetus, and together with other immune cells, likely play crucial roles in fetal development and maternal-fetal tolerance. In adults these cells have varied distribution across human tissues with distinct protein expression and transcriptional profiles depending on the tissue. There are also indications that ILCs have distinct developmental trajectories in different adult tissues. However, it remains unexplored how closely related ILCs are across human tissues.

To gain an understanding of how early fetal ILCs obtain these unique tissue profiles we investigated ILC composition and characteristics across paired fetal tissues. In study I we showed that NK cells and ILC3s have distinct distribution and gene expression profiles across fetal tissues. We also identified putative ILC and NK progenitors in the fetal intestine, suggesting that already first trimester tissues have unique ILC development which could contribute to the observed tissue differences.

We further explored NK cell developmental relationship across fetal tissues and with other immune cells in study II. Here we employed single cell sequencing to simultaneously study fetal immune cell gene expression and somatic mitochondrial mutations. We showed that somatic mitochondrial mutations are present already in the first trimester fetus and can be used to infer clonal relationships. The resulting clonal populations likely expanded from multipotent progenitor cells, as the majority of clones were present in multiple cell types and tissues. However, some clones showed biased towards NK cells, and specific tissues. Similarly, in vitro clonal expansion of most CD34+ progenitors generated two or more distinct cell types, though clones with a strong bias towards a single subset were also detected.

In study III, we investigated mechanisms of NK cells and T cell tissue homing during viral respiratory infections. We obtained peripheral blood from COVID-19 and influenza patients as well as publicly available single cell RNA sequencing data from bronchoalveolar lavage fluid from COVID-19 patients. Protein and gene expression analysis revealed that CXCR3+, CXCR6+ and/or CCR5+ NK cells and T cells are likely recruited to the lung during moderate infection. These cells also showed stronger activation profiles compared to those lacking chemokine receptors, indicating their universal role in airway infections.

List of scientific papers

I. Rødahl, I. E., M. A. Ivarsson, L. Loh, J. E. Mold, M. Westgren, D. Friberg, J. Mjösberg, N. K. Björkström, N. Marquardt, D. F. Nixon, and J. Michaëlsson. 2024. Distinct Tissue-Dependent Composition and Gene Expression of Human Fetal Innate Lymphoid Cells. Eur J Immunol. e202451150. https://doi.org/10.1002/eji.202451150

II. Rødahl, I. E., Q. Lin, J. Hård, C. J. Eriksson, M. Ivarsson, N. Marquardt, M. Westgren, E. Sundström, E. Åkesson, J. Mold, & J. Michaëlsson. 2025. Clonal diversity of fetal NK cells explored by somatic mitochondrial mutations. [Manuscript]

III. Brownlie, D., I. Rødahl, R. Varnaite, H. Asgeirsson, H. Glans, S. Falck- Jones, S. Vangeti, M. Buggert, H. G. Ljunggren, J. Michaëlsson, S. Gredmark-Russ, A. Smed-Sörensen, and N. Marquardt. 2022. Comparison of Lung-Homing Receptor Expression and Activation Profiles on NK Cell and T Cell Subsets in COVID-19 and Influenza. Front Immunol. 13: 834862. https://doi.org/10.3389/fimmu.2022.834862