Vα14+ NK T cells: A novel lymphoid cell lineage with regulatory function,☆☆,

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Abstract

A novel lymphoid lineage, NK T cells, was recently found. The NK T cells are the major population in the periphery comprising 5% of splenic T cells and 40% of bone marrow T cells. They express a unique TCR composed of invariant Vα14Jα281 and Vβ8.2 together with NK receptor (NKRPI). Surprisingly, the invariant Vα14+ TCR is exclusively expressed on NK T cells but not on conventional T cells. As the selective decrease in Vα14+ NK T cell population in the periphery is tightly correlated with autoimmune disease development, Vα14+ NK T cells control development of autoimmune diseases. We also found that Vα14 TCR gene rearrangement and transcripts were detected at an early embryogenesis (d9.5) before the thymus formation. Therefore NK T cells are in the distinct category from conventional T cells. The target of NK T cells is found to be CD1 (class 1b, monomorphic class I MHC-like molecule) present on bone marrow–derived cells and is killed by Fas-FasL interaction or perforin-mediated mechanisms. These results indicate that NK T cells consist of an immunoregulatory system different from defense system in terms of homogeneous repertoire, extrathymic development in early stage of gestation, and their regulatory functional role. (J Allergy Clin Immunol 1996;98:S263-9)

Section snippets

DOMINANT EXPRESSION OF INVARIANT Vα14 TCR

We have independently found, distinct from the discovery of thymic NK T cells, that an invariant TCRα, encoded by Vα14 and Jα281 segments with a one-base N-region, is expressed at an unusually high frequency in the peripheral tissues that comprise about 2% to 3% of the total TCRα-chains. This indicates a 106 times higher expression than expected (Fig. 1).9, 10 The invariant Vα14 TCR was first isolated from keyhold limpet hemocyanin (KLH)-specific suppressor T cell (Ts) hybridomas and was

THYMIC AND PERIPHERAL NK T CELLS

Recently, Lantz and Bendelac15 and Makino et al.16 demonstrated that the invariant Vα14 TCR is an antigen receptor exclusively expressed on NK T cells but not on other lymphoid cell lineages, including conventional αβ T cells. Apparent questions thus arise as to whether thymic NK T cells and peripheral Vα14+ T cells are identical or different subsets. In fact, several discrepant properties have been found between thymic and peripheral NK T cells. For example, Vα14+ T cells are found to be a

SELECTION OF PERIPHERAL Vα14+ NK T CELLS

The ligand and selection mechanisms of the invariant Vα14/Vβ8 TCR remain unclear. Accumulative evidence, however, strongly suggests that for the selection, peripheral Vα14+ NK T cells require a β2 microglobulin (β2m)-associated class I-like MHC molecule encoded by a nonMHC molecule, because β2m-deficient mice show the absence of invariant Vα14 TCR mRNAs.13 In addition, T cells expressing the invariant Vα14 TCR are present in mice lacking the transporter associated with antigen processing (TAP).

ESSENTIAL REQUIREMENT OF INVARIANT Vα14 TCR IN THE DEVELOPMENT OF NK T CELLS

Because NK T cells use only one invariant Vα14 TCR associated with Vβ8.2, we attempted to investigate their role in NK T cell development. For this purpose, we generated Vα14 TCR gene transgenic mice (Vα14 tg)17 Interestingly, FACS profiles of Vα14 tg and C57BL/6 spleen were similar except that Vα14 TCR expression increased in NK T cells in Vα14 tg mice (31% to 64%). Because allelic exclusion was not complete at the TCRα locus, TCRαs other than transgenic Vα14 TCR were likely to be expressed in

EXTRATHYMIC DEVELOPMENT OF Vα14+ NK T CELLS

In our previous studies, we found that athymic nude mice showed the dominant expression of invariant Vα14 TCR in the spleen.18 These results strongly suggested the extrathymic development of Vα14+ T cells. To address this issue in detail, we investigated the frequency of the circular DNA generated by the rearrangement of Vα14 and Jα281 gene segments. Circular DNA is an ideal probe for detecting the site of specific T cell development because one copy of the circular DNA reflects one

ORIGIN OF Vα14+ NK T CELLS

Lymphoid precursor cells are believed to arise from the yolk sac and migrate into the thymus.22 During lymphocyte development in the thymus, the TCR genes become functional by random rearrangements of variable and joining gene segments.23 The first productive TCR gene rearrangement occurs in the TCRγ genes and is detected in the thymus at day 13 of gestation just after thymus formation.24 The TCRβ gene is transcribed at day 15 before the TCRα genes, which are transcribed at day 17 of

Vα14+ NK T CELLS IN AUTOIMMUNE DISEASES

As already mentioned, two subpopulations, Vα14+ and Vα14- NK T cells, were detected in the peripheral NK T cell fraction. In the spleen, about 40% of the NK T cells were Vα14+ and 60% were Vα14-. Interestingly, a selective reduction in Vα14+ NK T cells was observed in autoimmune prone mice with different genetic backgrounds (lpr, gld, and BWF1 mice).26 The reduction in the number of Vα14+ NK T cells occurred approximately 4 weeks after birth and the Vα14+ NK T cells completely disappeared 10

Vα14+ NK T CELLS AS A NOVEL LYMPHOID LINEAGE DISTINCT FROM TRADITIONAL T CELLS

Judging from the above functional findings of Vα14 NK T cells, Vα14+ NK T cells probably consist of a novel immune system that mainly mediates a regulatory role, such as peripheral tolerance and immunologic surveillance. Moreover, their particular developmental properties, such as their extrathymic development in early embryogenesis, as well as their negative regulatory roles in the self-immune system that they strongly exhibit, indicate that Vα14+ NK T cells do not fit the definition of

Acknowledgements

We thank Ms Hiroko Tanabe for her excellent secretarial assistance.

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    From the Division of Molecular Immunology, Center for Biomedical Science, School of Medicine, Chiba University, Chiba.

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    Reprint requests: Masaru Taniguchi, MD, PhD, Division of Molecular Immunology, Center for Biomedical Science, School of Medicine, Chiba University, 1-8-1 Inohana, Chuoku, Chiba Japan 260.

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