Using CD1d-deficient mice and wild-type mice as a control, two research groups, compared the levels of humoral response against the CS protein upon immunization with radiation-attenuated sporozoites ofP. cells and CD4+ and CD8+ T cells. A significant proportion of NKT cells, called type I NKT cells, express an invariant T cell receptor (invTCR), characterized in mice by V14-J18 and V8.2, V7, or V2, and in humans by V24-J18 and V11, although the chain can be somewhat variable. ThisinvTCR recognizes lipid-based antigens in the context of CD1d molecules, Pecam1 an MHC Class I-like molecule expressed on antigen presenting cells (APCs) and other cell types. A second subgroup of CD1d-restricted NKT cells, also called type II NKT cells, utilizes other, more diversified TCRs to recognize CD1d molecules. NKT cells develop in the cortical thymus and undergo selection by CD1d molecules on cortical thymocytes [Reviewed in1]. NKT cells are known to play a role in cancer surveillance, largely through their ability to activate natural killer cells upon binding lipid-based tumor antigens [2,3]. NKT cells were initially discovered based on the finding that a novel glycolipid compound, -galactosyl ceramide (-GalCer), had anti-tumor activity [4]. Mechanistic studies elucidated that -GalCer binds CD1d and then -GalCer-CD1d complex activates NKT cells through theirinvTCR, leading to secondary activation of Vitamin K1 NK cells, DCs, and other leukocytes. -GalCer has been used in humans as a potential therapy for cancer [5-10]. NKT cells also play a role in suppressing autoimmune disease. Circulating numbers of NKT cells are decreased in patients with certain autoimmune diseases, such as diabetes, lupus, and multiple sclerosis [reviewed in11,12]. Understanding the role of NKT cells in cancer and autoimmunity may yield promising new therapies. NKT cells bridge the adaptive and innate immune responses to foreign lipid antigens. Known exogenous NKT cells ligands, which bind CD1d molecules and trigger activation of NKT cells through theirinvTCR, include -linked glycosphingolipids fromSphingomonas[13-16], galactosyl diacylglycerols fromBorrelia burgdorferi(b. Vitamin K1 burgdorferi) [13-16], lipophosphoglycan (LGP) onLeishmania donovani(l. donovani) [17] and phosphatidylinositol tetramannoside (PIM4) fromMycobacterium leprae (m. leprae)[18]. Upon binding CD1d molecules, these ligands are Vitamin K1 recognized byinvTCR expressed by NKT cells and rapidly activate both NKT cells and APCs. Given the broad range of known NKT cell function, this article is focused on the role of NKT cells in infection and immunity against two major global pathogens, human immunodeficiency virus (HIV) and malaria. == 2. NKT Cells in Malaria == == 2.1 Role of NKT cells in protective immunity against malaria == The role of NKT cells in protective immunity against malaria was first implicated in a study by Schofield et al [19]. In this study, CD1d-deficient mice that lack NKT cells, as well as wild-type control mice, were Vitamin K1 immunized twice with sporozoites of a rodent malaria parasite,Plasmodium berghei, and it was found that the level of humoral response against the circumsporozoite (CS) protein was strongly diminished in CD1d-deficient mice compared to wild-type mice. The study further demonstrated that glycosylphosphatidylinositol (GPI) purified from blood stages of a human malaria parasite,Plasmodium falciparum, was able to stimulate murine CD4+ NKT cellsin vitro, suggesting that CD4+ NKT cells act as a helper T cell to facilitate the production of anti-CS antibody by B cellsin vivo[19]. The role of NKT cells as a helper T cell against anti-malarial humoral responsein vivo, however, was later questioned by two independent studies [20,21]. Using CD1d-deficient mice and wild-type mice as a control, two research groups, compared the levels of humoral response against the CS protein upon immunization with radiation-attenuated sporozoites ofP. yoeliiorP. berghei, respectively. In the first study, performed by our group [20], it was shown that the level of anti-CS antibody response was not affected by the absence of CD1d molecules regardless of the genetic background of mice, i.e. BALB/c and C57BL/6, but was almost Vitamin K1 completely abolished in MHC-II-deficient mice. The second study by Romero et al [21] further demonstrated that both the level of humoral response against malaria and.
