| Natural killer T lymphocytes (NKT cells) are a small, but potent, subset of the circulating T lymphocytes. They can produce large amounts of cytokines that stimulate the surrounding cells, amplifying immune responses in the process. NKT cells recognize lipid and glycolipid antigens presented by an alternative antigen presenting molecule, CD1d. NKT cells also exhibit a property called autoreactivity; they are stimulated by lipids presented on CD1d molecules in the absence of exogenously added lipids. What these antigens are, however, is one of the big questions in the field. Here we have identified ligands eluted from secreted human CD1d molecules and analyzed the responses of NKT cell clones to those ligands. Human CD1d ligands identified included sphingolipids and mono-, di-, and tetra-acylated phospholipid species. Of the ligands eluted, only the mono-acylated phospholipid, lyso-phosphatidylcholine (LPC), elicited responses from the majority of NKT cell clones tested. A related molecule that is structurally similar to LPC, called lyso-sphingomyelin, was also recognized by NKT cell clones, indicating that features shared between LPC and LSM may contribute to NKT cell recognition.;NKT cell responses may also be impacted by the regulation of CD1 expression. In addition to CD1d, humans also possess other CD1 isoforms. CD1a, CD1b, and CD1c. These isoforms can be co-expressed on the same antigen presenting cell as CD1d, and can also bind lipid antigens and stimulate other CD1-restricted T cells. Our collaborators have identified cardiolipin and lyso-phosphatidic acid, two components of human serum, as modulators of CD1 expression, which occurs through the activation of the transcription factor PPAR1. What impact these other isoforms of CD1 have on the responses of NKT cells, however, is poorly understood. It is possible that they sequester antigen away from CD1d resulting in decreased NKT cell responses, or they could present antigen to NKT cells, contributing to some of the observed responses. Here we have shown that NKT cells can recognize the same antigen presented by both CD1d and the other CD1 isoforms, but that NKT cell responses to antigen presented by the other CDI isoforms were weak, in comparison with CD1d-mediated antigen presentation. |
