Deficiencies in enzymes of the lysosomal glycosphingolipid degradation pathway or in lysosomal lipid transfer proteins cause an imbalance in lipid metabolism and induce accumulation of certain lipids. A possible impact of such an imbalance on the presentation of lipid antigens to lipid-reactive T cells has only been hypothesized but not extensively studied so far. Here we demonstrate that presentation of lipid antigens to, and development of, lipid-reactive CD1d-restricted NKT cells, are impaired in mice deficient in the lysosomal enzyme b-galactosidase (bGal) or the lysosomal lipid transfer protein Niemann-Pick C (NPC) 2. Importantly, the residual populations of NKT cells selected in bGal -/-and NPC2 -/-mice showed differential TCR and CD4 repertoire characteristics, suggesting that differential selecting CD1d:lipid antigen complexes are formed. Furthermore, we provide direct evidence that accumulation of lipids impairs lipid antigen presentation in both cases. However, the mechanisms by which imbalanced lipid metabolism affected lipid antigen presentation were different. Based on these results, the impact of lipid accumulation should be generally considered in the interpretation of immunological deficiencies found in mice suffering from lipid metabolic disorders.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2007/37160_s.pdf IntroductionDefects in lysosomal lipid trafficking or degradation result in a severe imbalance of lipid metabolism. Little is known about the consequences of such an imbalance on the presentation of lipid antigens to lipid-reactive T cells, e.g., the important immunoregulatory invariant (i) NKT cell subset (Va14i and Va24i NKT cells in mice and humans, respectively), which recognizes glycolipid antigens presented by the MHC class I-like molecule Abbreviations: a-GalCer: a-galactosylceramide (KRN7000) Á a/bGal: a/b-galactosidase Á DN: CD4 -CD8 -double negative Á DP: CD4 + CD8 + double positive Á Hex: hexosaminidase Á HSA: heat-stable Ag Á i: invariant Á iGb3: isoglobotrihexosylceramide Á NB-DNJ: N-butyldeoxynojirimycin Á NPC: NiemannPick C Eur. J. Immunol. 2007Immunol. . 37: 1431Immunol. -1441 CD1d. In mice, the TCR of Va14i NKT cells is composed of an invariant Va14-Ja18 chain, paired preferentially with a restricted b chain, mostly containing Vb8.2 or Vb7 (the human equivalents are Va24-Ja18 and Vb11) [1][2][3][4]. Va14i NKT cells are implicated in the regulation of antitumor immunity, antimicrobial responses, and the balance between tolerance and autoimmunity [5,6]. Va14i NKT cells, which can be either CD4 + or CD4 -CD8 -double negative (DN), are a thymus-dependent population derived from CD4 + CD8 + double-positive (DP) thymocytes [7][8][9][10][11]. Different maturation stages of developing thymic Va14i NKT cells have been described, characterized by the sequential acquisition of CD44 and NK1.1 in C57BL/6 mice [12][13][14]. Unlike conventional MHC-dependent T cells, Va14i NKT cells are not positively selected by thymic epithelial cell...

Boron neutron capture therapy (BNCT) is an anticancer therapy based on the incorporation of (10)B in tumors, followed by neutron irradiation. Recently, the synthesis and delivery of new boronated compounds have been recognized as some of the main challenges in BNCT application. Here, we report on the use of liposomes as carriers for BNCT active compounds. Two carborane derivatives, i.e., o-closocarboranyl beta-lactoside (LCOB) and 1-methyl-o-closocarboranyl-2-hexylthioporphyrazine (H(2)PzCOB), were loaded into liposomes bearing different surface charges. The efficacy of these formulations was tested on model cell cultures, that is, DHD/K12/TRb rat colon carcinoma and B16-F10 murine melanoma. These induce liver and lung metastases, respectively, and are used to study the uptake of standard BNCT drugs, including borophenylalanine (BPA). Boron concentration in treated cells was measured by alpha spectrometry at the TRIGA mark II reactor (University of Pavia). Results showed high performance of the proposed formulations. In particular, the use of cationic liposomes increased the cellular concentration of (10)B by at least 30 times more than that achieved by BPA.

Sulfogalactosylglycerolipid (SGG, aka seminolipid) is selectively synthesized in high amounts in mammalian testicular germ cells (TGCs). SGG is an ordered lipid and directly involved in cell adhesion. SGG is indispensable for spermatogenesis, a process that greatly depends on interaction between Sertoli cells and TGCs. Spermatogenesis is disrupted in mice null for Cgt and Cst, encoding two enzymes essential for SGG biosynthesis. Sperm surface SGG also plays roles in fertilization. All of these results indicate the significance of SGG in male reproduction. SGG homeostasis is also important in male fertility. Approximately 50% of TGCs become apoptotic and phagocytosed by Sertoli cells. SGG in apoptotic remnants needs to be degraded by Sertoli lysosomal enzymes to the lipid backbone. Failure in this event leads to a lysosomal storage disorder and sub-functionality of Sertoli cells, including their support for TGC development, and consequently subfertility. Significantly, both biosynthesis and degradation pathways of the galactosylsulfate head group of SGG are the same as those of sulfogalactosylceramide (SGC), a structurally related sulfoglycolipid important for brain functions. If subfertility in males with gene mutations in SGG/SGC metabolism pathways manifests prior to neurological disorder, sperm SGG levels might be used as a reporting/predicting index of the neurological status.

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