Tbet promotes CXCR6 expression in immature natural killer cells and natural killer cell egress from the bone marrow.

Antonia O Cuff,Victoria Male,Rachel Golub,Thibaut Perchet,Simone Dertschnig

doi:10.1111/imm.13204

Abstract

SummaryTbet‐deficient mice have reduced natural killer (NK) cells in blood and spleen, but increased NK cells in bone marrow and lymph nodes, a phenotype that is thought to be the result of defective migration. Here, we revisit the role of Tbet in NK cell bone marrow egress. We definitively show that the accumulation of NK cells in the bone marrow of Tbet‐deficient Tbx21 −/− animals occurs because of a migration defect and identify a module of genes, co‐ordinated by Tbet, which affects the localization of NK cells in the bone marrow. Cxcr6 is approximately 125‐fold underexpressed in Tbx21 −/−, compared with wild‐type, immature NK cells. Immature NK cells accumulate in the bone marrow of CXCR6‐deficient mice, and CXCR6‐deficient progenitors are less able to reconstitute the peripheral NK cell compartment than their wild‐type counterparts. However, the CXCR6 phenotype is largely confined to immature NK cells, whereas the Tbet phenotype is present in both immature and mature NK cells, suggesting that genes identified as being more differentially expressed in mature NK cells, such as S1pr5, Cx3cr1, Sell and Cd69, may be the major drivers of the phenotype.

Highlights

Tbet was originally described as the key transcription factor directing Th1 lineage commitment (Szabo et al, 2000)
In order to better understand the requirement for Tbet in NK cell development and migration, we examined the bone marrow of Tbx21-/- mice, further subdividing the mature NK cell population into a CD27+ subset of intermediate maturity, which for simplicity is sometimes called “mNK1”, and a more mature CD27- subset called “mNK2” (Kim et al, 2002; Chiossone et al, 2009; Goh & Huntington, 2017) (Fig. 1a)
NK cells are less able to leave the bone marrow in the absence of Tbet Previous reports attribute the bone marrow accumulation of Tbet-deficient NK cells to a defect in migration involving S1PR5, since S1pr5 mRNA is underexpressed in Duane NK cells, S1pr5-/mice phenocopy the accumulation of NK cells in the bone marrow of Duane mice and in S1pr5-/mice the accumulation is caused by a migration defect (Jenne et al, 2009; Walzer et al, 2007; Mayol et al, 2011)

Summary

Introduction

Tbet was originally described as the key transcription factor directing Th1 lineage commitment (Szabo et al, 2000). In two strains of Tbetdeficient mice - Tbx21-/- (Townsend et al, 2004) and Duane, in which a point mutation in Tbx leads to underexpression of the protein by a factor of approximately four-fold (Jenne et al, 2009) - NK cell number, maturation status and function are abnormal Both strains of Tbet-deficient mice have reduced NK cells in blood and spleen, but increased NK cells in the bone marrow and lymph nodes (Townsend et al, 2004; Jenne et al, 2009). A defect in NK cell migration in the absence of Tbet has not yet been formally shown, nor have potential mediators of egress other than S1PR5 been identified

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Results

Discussion

Conclusion