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Novel pathway of thymus-dependent NK cell development

University of British Columbia

Natural killer (NK) cells are the major lymphocytes of the innate immune system, but their developmental pathway is not fully defined. It is commonly assumed that all NK cells develop in the bone marrow. In this thesis, I describe a novel thymus-dependent pathway of NK cell development that is specific to those in the thymus and lymph nodes. Microarray analysis revealed TCRγ mRNA expression in NK cells. Genomic and RT-PCR showed that some NK cells have rearranged TCRγ genes while TCRβ and TCRδ genes are in germline order. NK cells with rearranged TCRγ ( Tcrγ⁺ NK cells) were absent in nude mice indicating that they are thymus-dependent. Approximately half of thymus NK cells have rearranged TCRγ genes and in vitro cultures of immature thymocytes (double negative (DN)1 and DN2 progenitors) produced Tcrγ⁺ NK cells, strongly suggesting that these are the thymus-dependent NK cell progenitors in vivo. Thymus NK cells are CD94/NKG2[sup hi] Ly49[sup lo] Mac-1[sup lo] IL-7Rα[sup hi] and they have normal cytotoxicity levels but reduced IFNγ production. By using TCRγ gene rearrangement as a marker of thymus-dependent NK cells, we showed that they are also present in lymph nodes (LNs) but in no other tissues tested. NK progenitors similar to immature thymocytes were found in LNs and LN Tcrγ⁺ NK cells and LN progenitors were also absent in nude mice. In vitro cultures and preliminary in vivo studies suggest that the NK progenitors in the LN give rise to mature NK cells. The results suggest that immature thymocytes migrate to LNs and differentiate into NK cells. It is likely that the thymus-dependent NK cells play a special role in the immune response since their phenotype is unique. Finally, this study suggests that multiple pathways of NK cell commitment exist in multiple tissues. The differences in tissue environment may influence the phenotype and function of NK cells, resulting in multiple subsets of NK cells throughout the body.

Text

2011-02-10

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http://hdl.handle.net/2429/31179

Genetics

University of British Columbia

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