Natural killer T cells: Know thyself

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Abstract
There are two main reasons why natural killer T (NKT) cells fascinate immunologists. First, they exhibit a unique mélange of properties found in innate immune cells as well as the properties of conventional T cells, part of adaptive immunity (1–4). Second, NKT cells exercise a determining influence on a variety of immune responses in mice, ranging from autoimmunity to their response to tumors and infections (1–4). Because NKT cells have a limited diversity of their T cell antigen receptor (TCR) α chains, they are often called invariant (i)NKT cells (3, 5). iNKT cells recognize glycolipid antigens from certain bacteria that are presented by CD1d, a nonpolymorphic antigen-presenting molecule (4), but this is not the entire story. Although students are taught that lymphocytes must be tolerant of self, this is not the case for iNKT cells, because there is evidence that iNKT cells are activated as a result of contact with self-antigens in the thymus (1–3, 6). Self-reactivity may allow iNKT cells to respond rapidly, not by specifically recognizing a panoply of microbial antigens but by responding to a secondary signal of infection with a very limited TCR diversity. It is widely believed that the same self-antigens expressed in the thymus activate the mature cells. These mature cells are in contrast to conventional T cells, which are positively selected by weak TCR interactions and would be negatively selected by TCR agonists. Therefore, although iNKT cells obey the ancient aphorism “to know thyself,” the chemical definition of the self-antigen has been elusive. It has been proposed that a single glycosphingolipid (GSL), isoglobotrihexosylceramide (iGb3), is required for iNKT cell differentiation in the thymus (7) and activation in the periphery (8, 9). GSLs are glycolipids that contain a ceramide …