Role of CD1d-restricted NKT cells in microbial immunity.

The discovery that T cells recognize lipid and glycolipid molecules presented by CD1 proteins has greatly expanded the number of potential microbial antigens targeted by the immune system following infection. The ability of CD1d-restricted NKT cells to activate innate and adaptive immune responses has led to the idea that these cells can modulate immunity to infectious agents. In addition, CD1d-restricted NKT cells may directly contribute to host resistance as they express a variety of effector molecules that could mediate an antimicrobial effect. Although much has been learned about CD1d-restricted NKT cells through the use of the synthetic antigen -galactosylceramide ( GalCer), the field has been hampered by the paucity of information about the physiological self and microbial lipid antigens that can be presented by CD1d. Here we review the literature stating that CD1d-restricted NKT cells contribute to host defense against microbial pathogens. The biology of CD1d and CD1d-restricted T cells. The CD1 proteins are antigen-presenting molecules that present lipid antigens to T cells. Similar in structure to major histocompatibility complex (MHC) class I, the CD1 heavy chain associates with 2 microglobulin to form a heterodimer that is expressed on the cell surface of the antigen-presenting cell (APC) (76). However, in contrast to MHC molecules, CD1 proteins have a deep hydrophobic antigen binding pocket that is well suited to binding lipid antigens (35, 96). The human CD1 locus is located on chromosome 1 and contains five distinct genes: CD1A, -B, -C, -D, and -E. Based on sequence homology, the CD1 family is divided into group 1 (CD1a, -b, and -c) and group 2 (CD1d) proteins (18). The group 1 CD1 proteins are found in a variety of mammalian species, including humans, but not in mice or rats (78). In contrast to group 1 CD1, CD1d is found in humans, rodents, and most mammalian species that have been studied. The discovery that CD1d is the antigenpresenting molecule that restricts NKT cells provided an important insight into the function of group 2 CD1 (12). Murine NKT cells were originally defined as a population of T cells that express an invariant T-cell receptor (TCR) chain (V 14/ J 281) in association with V 2, -7, or -8 and express the NK1.1 antigen (NKR-P1C), a cell surface C-type lectin that is also expressed by NK cells and activated T cells (13, 60). Phenotypically, NK1 T cells are either CD4 CD8 or CD4 CD8 and this T-cell population represents a major fraction of the mature T cells in thymus, nearly 50% of / TCR T cells in liver and up to 5% of splenic T cells, but are rare in lymph nodes (LN). These cells are notable for their rapid production of interleukin 4 (IL-4) and gamma interferon (IFN) after activation with anti-CD3 monoclonal antibody (MAb). Human invariant V 24-J Q/V 11T cells are phenotypically and functionally homologous to murine NK1 T cells and, like their murine counterparts, are CD1d restricted and express NKRP1. The degree of conservation is remarkable, as mouse CD1drestricted T cells can recognize human CD1d and vice versa, establishing mice as an excellent model for the study of human CD1d and NKT cells (15). Not surprisingly, defining NKT cells has become more complicated. Conventional human and murine / TCR and / TCR T cells can also express NK cell markers, especially following infection. For example, NKT cells have been detected in CD1d knockout ( / ) and J 281 / mice, showing that coexpression of the / TCR-CD3 complex with the NK1.1 antigen is not sufficiently specific to identify CD1drestricted NKT cells. To complicate matters further, two subsets of CD1d-restricted T cells have been identified: one that expresses the invariant TCR (i.e., invariant NKT cells or iNKT) and one that uses a diverse TCR repertoire (diverse NKT cells) (9). The synthetic ligand, GalCer (see below), activates iNKT cells but not diverse NKT cells. Although exceptions may emerge, this has been a useful distinction, as iNKT cells can be specifically identified by flow cytometry with GalCer-loaded CD1d-multimers that bind to the invariant TCR (34, 41). The in vivo function of the two NKT cell subsets can sometimes be distinguished, since CD1d / mice lack both subsets of NKT cells, while J 281 / mice lack only iNKT cells. In this review, the more inclusive term “CD1d-restricted NKT cell” will be used to include both invariant and diverse CD1d-restricted NKT cells. When appropriate, the term “iNKT” cell will be used to refer to NKT cells that stain with GalCer-loaded CD1d tetramers, respond to GalCer, or are absent from J 281 / mice. What antigens are presented by CD1d? A significant advance in understanding the biology of the group 1 CD1 proteins (CD1a, -b, and -c) was the finding that these proteins can present foreign microbial lipid antigens, including several mycobacterial antigens (6, 7, 71, 80). In contrast, the antigens presented by CD1d remain poorly characterized. CD1d-restricted NKT cells were first described as self-reactive, as both human and murine CD1d-restricted NKT cells can recognize * Corresponding author. Mailing address: Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Smith Building, Room 516C, One Jimmy Fund Way, Boston, MA 02115. Phone: (617) 525-1033. Fax: (617) 525-1010. E-mail: [email protected] .harvard.edu.