Toxoplasma gondii infection drives conversion of NK cells into ILC1-like cells

Abstract

Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here, we describe Toxoplasma gondii infection converts NK cells into ILC1-like cells that are distinct from both steady-state NK cells and ILC1s in uninfected mice. These cells were Eomes-dependent, indicating that NK cells can give rise to Eomes– Tbet-dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly expand current concepts of NK cells, ILCs, and their potential conversion.

Tbet promotes NK cell egress from the bone marrow and CXCR6 expression in immature NK cells

“…Our observations of CXCR6-deficient mice further support the idea that this is an NK cell and not an ILC1 phenomenon, since in adult life CXCR6-deficient bone marrow progenitors are somewhat less able to reconstitute the NK cell compartment than their CXCR6-sufficient counterparts, whereas they are equally able to reconstitute the adult ILC1 compartment. Indeed if, as some recent studies have suggested, NK cells and ILC1 do not form separate lineages, it will not be possible to define phenomena as pertaining to NK cells separately from ILC1 (Gao et al, 2017;Cortez et al, 2017, Park et al, 2019Xu et al, 2019). Overall, we have shown that Tbet is required for NK cells to leave the bone marrow in a cell-intrinsic manner.…”

“…More recently, it has become clear that Tbet also drives differentiation and memory cell generation in a number of lymphocyte lineages (Kallies and Good-Jacobson, 2017) as well as being required for the development and survival of ILC1 (Spits et al, 2013). There is still debate about the extent to which ILC1 form a separate lineage from NK cells (Vivier et al, 2018;Gao et al, 2017;Cortez et al, 2017;Park et al, 2019;Xu et al, 2019), with one key factor that distinguishes NK cells from ILC1 being the greater extent to which ILC1 depend upon Tbet for their development (Sojka et al, 2014;Daussy et al, 2014). Nevertheless, Tbet-deficient mice do display defects in NK cell number, maturation status and function (Townsend et al, 2004;Jenne et al, 2009).…”

NK cells negatively regulate CD8 T cells to promote immune exhaustion and chronicToxoplasma gondiiinfection

“…The significant increase in KLRG1+ NK cells and NKG2A+ NK cells suggested these cells were being enriched within the NK cell compartment. A recent study suggests that CD49a+ ILC1 may develop from NK cells and exhibit this phenotype in the liver of mice infected with the vaccine strain of T. gondii cps1-1 and a different limited cyst forming type II strain Prugniaud [50]. Therefore to determine if this was also occurring in NK cells in the spleens after infection with the vaccine strain, we infected mice with cps1-1 and 5 weeks later assayed the spleen cells for CD94+NKG2A+ NK cells.…”

Differentiation of c‐Kit + CD24 + natural killer cells into myeloid cells in a GATA‐2‐dependent manner

“…37 NK cells are converted into type 1 ILCs in the tumor environment and Toxoplasma gondii infection. [38][39][40] These natural examples indicate that the differentiation of NK cells into myeloid cells is not an improbable phenomenon. However, differentiated cells are commonly converted into adjacent lineages during the naturally occurring lineage reprogramming between immune cells.…”