-Ontogeny:The origin and development of an individual organism from embryo to adult. Also called ontogenesis.(dictionary.com)
-Natural Killer Cells:
a large granular lymphocyte capable of killing a tumor or microbial cell without prior exposure to the target cell andwithout having it presented with or marked by a histocompatibility antigen called also NK cell (medical dictionary, dictionary.com)
NK cells
Unique features of NK cell development during ontogeny revealed in studies of RAG-1-deficient mice
Benedict J Chambers
1 and Hans-Gustaf Ljunggren
1
1Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm 141 86, Sweden. E-mail: hans-gustaf.ljunggren@ki.se
Natural killer (NK) cells link early innate immune responses with adaptive immune responses. ‘Adaptive’ immune cells, that is, the T- and B-lymphocytes, express clonally distributed receptors, the expression of which is dependent on the recombination activation genes-1 (RAG-1) and RAG-2. In the absence of RAG-1 and/or RAG-2 proteins, T- and B-cell receptors cannot be formed and the cells fail to undergo normal development.
1 In contrast, NK cells are equipped with a set of germline-encoded receptors whose expression is not dependent on the RAG-1 and/or RAG-2 proteins. Adult Rag-1- and Rag-2-deficient mice have been thought to have virtually normal numbers of NK cells with no general functional deficiency.
2 However, Andrews and Smyth
3 now, on careful analysis, observed marked differences in accumulation of NK cell subsets in different organs of neonatal Rag-1-deficient mice compared with corresponding wild-type mice. Importantly, these new observations reveal interesting insights into organ-specific NK cell development during ontogeny in mice.
What led Andrews and Smyth to the present studies was the previous identification of four discrete subsets of mouse NK cells based on analysis of CD27 and CD11b expression.
4 The most immature subset is CD27lo/CD11b− cells, followed by CD27hi/CD11b−, CD27hi/CD11bhi and CD27lo/CD11bhi subsets. The CD27hi/CD11bhi subset of NK cells exhibits a profound cytokine-producing capacity, whereas the CD27lo/CD11bhi subset represents a terminally mature subset with high expression of major histocompatibility complex class I-recognizing Ly49 molecules. On the basis of this division of murine NK cell subsets, Andrews and Smyth set out to characterize NK cells in different organs during ontogeny in C57BL/6 mice. They found that NK cells in the bone marrow, spleen and lung of neonatal mice exist as immature CD27hi/CD11lo cells. The first appearance of mature CD27lo/CD11bhi cells in these organs occurs at 3 weeks of age and maturation is complete by 8 weeks of age. In contrast, they found, strikingly, that maturation of liver NK cells is ‘essentially finished’ by 2 weeks of age.
In the course of these studies, they made the interesting observation that patterns of NK cell subsets were altered in Rag-1-deficient mice compared with wild-type mice. Bone marrow and spleen NK cells were absent in neonatal Rag-1-deficient mice, and an overrepresentation of a precursor (CD27lo/CD11b−) NK cell subset was found in the bone marrow of neonatal Rag-1-deficient mice.
3 These data argue for a role of RAG-1 in NK cell development. However, as Rag-1-deficient mice lack T and B cells, the possibility that the effects observed could be (in part) an indirect consequence of the absence of T and/or B cells cannot be excluded. Although the authors do not exclude this possibility, they provide indirect evidence against it. NK cell development in mice lacking either normal T cells, NKT cells or B cells did not mimic the phenotype observed in Rag-1-deficient mice.
3 These results suggest that the absence of isolated subsets of adaptive immune cells (T, NKT or B cells) in Rag-1-deficient mice is not responsible for the absence of NK cells in the bone marrow and spleen during early ontogeny. Similarly, the overrepresentation of immature NK cells in the bone marrow of Rag-1-deficient mice cannot easily be explained by the absence of adaptive immune cells. This observation led Andrews and Smyth to suggest that the RAG-1 protein may regulate NK cell development in the bone marrow but not in the liver. In other words, NK cell development may occur independently between the bone marrow and liver as a possible consequence of differential precursor development, which is RAG-1-dependent (
Figure 1). The present findings thus highlight the liver as a possible independent source of NK cells, generating an independent pool of NK cells with specific characteristics.
5,
6
Figure 1.
NK cell development may occur independently in the bone marrow and in the liver during ontogeny as a consequence of precursor-development dependence on RAG-1. The present findings highlight the liver as a possible source of RAG-1-independent NK cells, generating a pool of NK cells with specific characteristics. In the absence of bone marrow-derived NK cells, such as in neonatal RAG-1-deficient mice, liver-derived NK cells may seed other organs including the bone marrow and spleen.
Full figure and legend (122K)
Several important points are raised in this study. One is that full maturation of the NK cells does not occur in most organs until 8 weeks of age. This is of particular importance as several studies with, for example, new strains of genetically altered mice are often analyzed early in life for logistic and other related reasons. Andrews and Smyth bring up the possibility that studies on NK cells in mice should be standardized between laboratories and conducted on mice that are at least 8 weeks of age. This argument is indeed very well made. As pointed out, the present findings also bear relevance for vaccination of young mice, particularly in settings in which NK cells may influence the outcome.
7
The present data suggest the possibility that RAG-1 might have a more direct role in NK cell development. It is not, however, easy to envisage what this role would be, or how it would work. As RAG transcripts are not detected in mature NK cells,
8 a role for RAG in NK cell development must occur during linage commitment, as speculated by Andrews and Smyth.
3 Studies have demonstrated that RAG-1/V(D)J activity occurs in lymphoid-primed progenitors, which, on transfer, can give rise to NK cells.
9,
10 Given that most conventional NK cells in the bone marrow derive from these precursors,
11 Andrews and Smyth reason that it is perhaps not surprising that NK cells cannot be detected in the bone marrow of neonatal mice.
3 In contrast to the bone marrow, Rag-1-expression in fetal liver progenitors is not restricted to cells of the lymphoid lineage,
12 suggesting that fetal lymphopoiesis is different in the liver than in the bone marrow. Accumulation of an immature (CD27lo/CD11b−) precursor population into the bone marrow of Rag-1-deficient mice indicates that liver NK cell precursors may seed into the other organs to compensate for the absence of bone marrow-derived NK cells. In support of this notion, Andrews and Smyth observed that accumulation of total and terminally mature NK cells in the bone marrow and spleen of Rag-1-deficient mice occurs ‘identically’ to that observed in the liver.
3 In conclusion, the present findings suggest that NK cell development in the absence of RAG-1 is altered significantly, and raise the interesting suggestion of an accumulation of liver-derived NK cells in other organs. These observations should encourage further studies with respect to NK cell development during ontogeny.
Immunology and Cell Biology (2010) 88, 105–106; doi:10.1038/icb.2009.103; published online 15 December 2009
References
Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 1992; 68: 869–877.
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Mombaerts P, Mizoguchi E, Ljunggren HG, Iacomini J, Ishikawa H, Wang L et al. Peripheral lymphoid development and function in TCR mutant mice. Int Immunol 1994; 6: 1061–1070.
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Andrews DM, Smyth MJ. A potential role for RAG-1 in NK cell development revealed by analysis of NK cells during ontogeny. Immunol and Cell Biol (e-pub ahead of print 1 December 2009).
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