Development of group-3 innate lymphoid cells via Tox2-dependent pathway in gut.

Abstract

Abstract Innate lymphoid cells (ILCs) are immune cells that lack specific antigen receptors but possess similar effector functions as T cells. Interestingly, ILCs and T cells express many of the same transcription factors. One such factor is TOX, a sequence non-specific nuclear transcriptional regulator that is crucial for development of both CD4 T cells and ILCs. TOX-deficient mice have significantly reduced number of early innate lymphoid progenitors (EILP) and ILC progenitors (ILCP). Consequently, the mature NK cells, ILC1, ILC2 and ILC3 subsets are greatly reduced in Tox−/− mice. Interestingly ILC3 numbers in gut are not reduced by the absence of TOX. We have discovered that TOX2, another member of the TOX family of HMG-box proteins, is highly expressed in ILC precursors. We generated Tox2−/− mice and found they have reduced ILC3 in gut; however, ILC3 cells in spleen or lymph node are intact. We also observed ILCP in fetal gut and adult gut were significantly reduced in Tox2−/−mice suggesting TOX2 is required for gut ILC3 development. However, ILCP numbers in adult gut of Tox−/− mice were unaffected. We are currently performing single-cell RNA-sequencing on gut ILC3 from Tox2−/− and Tox−/− mice to transcriptionally characterize these cells and to identify the heterogeneity within the ILC3 population. Taken together, our results indicate the existence of at least two pathways of ILC development: a central pathway in bone marrow and fetal liver that is TOX dependent; and a peripheral pathway of development of ILC3 in gut that requires TOX2.