Natural killer T cells and rheumatoid arthritis: friend or foe?

α-GalCer = α-galactosylceramide, MHC = major histocompatibility complex, NKT = natural killer T cell, RA = rheumatoid arthritis, TCR = T cell receptor, Th = T helper. Natural Killer T (NKT) cells have been described as T lymphocytes expressing NK receptors such as NK1.1. This lymphocyte subset consists of several subpopu-lations, each with distinct characteristics [1, 2]. Unlike conventional T cells, the vast majority of mouse NKT cells recognize glycolipid antigens including α-galactosyl-ceramide (α-GalCer), a glycosphingolipid originally isolated from marine sponges that can not be found in mammalian cells [3]. α-GalCer is presented by an MHC class I like antigen presenting molecule, CD1d. Several studies have highlighted the unique features of NKT cells, because their T cell receptor (TCR) repertoire is highly skewed with an invariant TCR-α rearrangement, Vα14-Jα18. In humans, a similar NKT cell subset with an invariant TCR-α chain, Vα24, exists. Therefore, these cells are often referred to as Vαi NKT cells. A characteristic feature of Vαi NKT cells is their rapid production of large quantities of both Th1 and Th2 cytokines upon stimulation. These cells, therefore, may profoundly regulate the immune system: they may either enhance or suppress immune responses [4]. Several groups have investigated whether Vαi NKT cells are relevant for the pathogenesis of autoimmune diseases. There is evidence suggesting that Vαi NKT cells naturally influence autoimmunity and from other experiments it appeared that a vigorous but unnatural activation of Vαi NKT cells by α-GalCer is required to elicit their regulatory function. For example, in type 1 diabetes Vαi NKT cells are considered to be protective [5], although some conflicting reports exist [6, 7]. Vαi NKT cells are also considered to be of relevance in the pathogenesis of other autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus and experimental colitis although their precise role in these diseases remains unclear at present [4]. Few data exist on the putative role of Vαi NKT cells in the pathogenesis of rheumatoid arthritis (RA). It has been reported that RA patients have abnormalities in the number and function of Vαi NKT cells that are CD4 – CD8 – in peripheral blood lymphocytes compared to healthy individuals, suggesting a protective role for these cells in RA [8], although indirect effects induced by for example therapy have not been ruled out. Due to their immunomodulatory properties, manipulation of Vαi NKT cell mediated responses is an attractive potential therapeutic strategy for the …