The absence of invariant chain in MHC II cancer vaccines enhances the activation of tumor-reactive type 1 CD4<Superscript>+</Superscript> T lymphocytes

Activation of tumor-reactive T lymphocytes is a promising approach for the prevention and treatment of patients with metastatic cancers. Strategies that activate CD8⁺ T cells are particularly promising because of the cytotoxicity and specificity of CD8⁺ T cells for tumor cells. Optimal CD8⁺ T cell activity requires the co-activation of CD4⁺ T cells, which are critical for immune memory and protection against latent metastatic disease. Therefore, we are developing “MHC II” vaccines that activate tumor-reactive CD4⁺ T cells. MHC II vaccines are MHC class I⁺ tumor cells that are transduced with costimulatory molecules and MHC II alleles syngeneic to the prospective recipient. Because the vaccine cells do not express the MHC II-associated invariant chain (Ii), we hypothesized that they will present endogenously synthesized tumor peptides that are not presented by professional Ii⁺ antigen presenting cells (APC) and will therefore overcome tolerance to activate CD4⁺ T cells. We now report that MHC II vaccines prepared from human MCF10 mammary carcinoma cells are more efficient than Ii⁺ APC for priming and boosting Type 1 CD4⁺ T cells. MHC II vaccines consistently induce greater expansion of CD4⁺ T cells which secrete more IFNγ and they activate an overlapping, but distinct repertoire of CD4⁺ T cells as measured by T cell receptor Vβ usage, compared to Ii⁺ APC. Therefore, the absence of Ii facilitates a robust CD4⁺ T cell response that includes the presentation of peptides that are presented by traditional APC, as well as peptides that are uniquely presented by the Ii⁻ vaccine cells.     

Cathepsin E regulates the presentation of tetanus toxin C-fragment in PMA activated primary human B cells

Processing of antigens by proteases in the endocytic compartments of antigen presenting cells (APC) is essential to make them suitable for presentation as antigenic peptides to T lymphocytes. Several proteases of the cysteine, aspartyl and serine classes are involved in this process. It has been speculated, that the aspartyl protease cathepsin E (CatE) is involved in antigen processing in B cell line, monocyte-derived dendritic cells (DC) and murine DC. Here we show the expression of CatE in primary human B cells and DC, which was only elevated in B cells after induction with phorbol 12-myristate 13-acetate (PMA), resulted in enhanced presentation of tetanus toxin C-fragment (TTC) to the respective T cells. Inhibition of aspartyl proteases using pepstatin-A-penetratin (PepA-P), a highly efficient, cell-permeable aspartyl protease inhibitor, reduced significantly T cell activation in PMA activated B cells but not in PMA activated myeloid DC (mDC). Thus we suggest that CatE is important in the processing of TTC in primary human B cells.     

MHC及其在种群遗传学和保护遗传学中的应用

主要组织相容性复合体（major histocompatibility complex,MHC）是脊椎动物体内与免疫应答调节密切相关的一个基因家族,是基因组中多态性最丰富的区域。通过MHC的遗传变异分析可以提供物种的遗传多样性水平、进化历史和种群动态,以及种群遗传结构等信息,并在濒危物种饲养繁殖种群的遗传管理中有重要应用。 MHC and Its Application in the Population and Conservation Genetics YANG Guang,CHEN Xu-yan,REN Wen-hua,YAN Jie Institute of Genetic Resources,Nanjing Normal University,Nanjing 210097,China Abstract:The major histocompatibility complex (MHC),with the highest genetic polymorphism,is a cluster of genes involved in immune response regulation in the vertebrates.MHC can provide information such as population genetic diversity,evolutionary history and population dynamics,and population genetic structure etc.It can also be applied in the captive breeding programme for endangered vertebrate species. Key words：major histocompatibility complex (MHC);genetic diversity,population viability;population genetic structure;captive breeding     

Survival of heterotopic heart xenografts from Helisoma duryi,Planorbula armigera,and Planorbarius corneus in Biomphalaria glabrata (Pulmonata,Basommatophora, Planorbidae): evidence for phylogenetic relatedness?

Abstract. Heart xenografts from the pulmonate snail Helisoma trivolvis survive in Biomphalaria glabrata , whereas xenografts from most other pulmonate snail genera are rejected within 3 to 15 days. To test whether xenografts from snails closely related to H. trivolvis were also accepted, specimens of an albino strain of B. glabrata were implanted with hearts from H. duryi, Planorbula armigera , and Planorbarius corneus . The fate of implants was monitored for 180 days by measuring heartbeat and by histological analysis. All 3 types of implants survived beyond the 3 to 15 days required for the complete destruction of incompatible xenografts, suggesting a degree of physiological and immunological compatibility between B. glabrata and these donors. Among the 3 types of xenografts, all from H. duryi survived for the entire 180 days. Fewer grafts from P. armigera and P. corneus survived for prolonged periods, although some still were beating at 60 and 180 days post implantation (DPI) respectively, suggesting that a range of histocompatibility, and perhaps phylogenetic relatedness, with B. glabrata occurs within this group. Paradoxically, the initial hemocytic response by the recipient was strongest against grafts from H. duryi , the most compatible donor, while responses to grafts from P. armigera and P. corneus were mild or did not occur during the first 7 DPI. We used 2 albino strains of B. glabrata in these studies, and the data suggest slight differences in recipient strain compatibility.     

Reduced MHC variation in a threatened tuatara species

The relationship between neutral and adaptive genetic diversity is important to understand in assessing the implications of a population bottleneck. Fitness-related genes, such as those of the major histocompatibility complex (MHC), may be influenced by selection, and so retain diversity even when it is lost at neutral markers. We measured MHC class I variation in an archaic reptile species Sphenodon guntheri [North Brother Island (NBI) tuatara], which naturally occurs on one 4 ha island in Cook Strait, New Zealand, and has low levels of microsatellite diversity. MHC variation in S. guntheri was compared with microsatellite DNA variation, and with MHC variation in a large population of Sphenodon punctatus (Cook Strait tuatara) on Stephens Island. The NBI population shows significantly decreased levels of genetic diversity compared with the Stephens Island population. Only three different MHC sequences and three genotypes were found on NBI, compared with 15 sequences and 21 genotypes in a similar sample size from Stephens Island. Two sequences appear to be unique to the NBI population. The assortment of sequence variants into genotypes suggests strong gametic disequilibrium between two MHC class I loci in S. guntheri , and only two haplotypes that were present in Hardy–Weinberg proportions were identified. MHC diversity in NBI tuatara appears to be largely influenced by genetic drift, consistent with a recent population bottleneck. This may compromise the ability of this population to respond to novel disease threats.     

Tissue-Characteristic Expression of Mouse Proteome

The mouse is a valuable model organism for biomedical research. Here, we established a comprehensive spectral library and the data-independent acquisition–based quantitative proteome maps for 41 mouse organs, including some rarely reported organs such as the cornea, retina, and nine paired organs. The mouse spectral library contained 178,304 peptides from 12,320 proteins, including 1678 proteins not reported in previous mouse spectral libraries. Our data suggested that organs from the nervous system and immune system expressed the most distinct proteome compared with other organs. We also found characteristic protein expression of immune-privileged organs, which may help understanding possible immune rejection after organ transplantation. Each tissue type expressed characteristic high-abundance proteins related to its physiological functions. We also uncovered some tissue-specific proteins which have not been reported previously. The testis expressed highest number of tissue-specific proteins. By comparison of nine paired organs including kidneys, testes, and adrenal glands, we found left organs exhibited higher levels of antioxidant enzymes. We also observed expression asymmetry for proteins related to the apoptotic process, tumor suppression, and organ functions between the left and right sides. This study provides a comprehensive spectral library and a quantitative proteome resource for mouse studies.     

Joint Report of the First International Comparison Test on Swine Lymphocyte Alloantigens (SLA)

The first international comparison test on swine lymphocyte alloantigens (SLA) was held in Helsinki, Finland in July 1986. The results reported were based on a comparison of 157 alloantisera originating from six laboratories. The antisera were tested against a selected panel of 264 lymphocyte samples belonging to four laboratories. The most common breeds in Europe were chosen for this first comparison test (Landrace and Large White). Eighteen of the 31 previously known specificities were confirmed and a new nomenclature was established.     

Joint Report of the Third International Bovine Lymphocyte Antigen (BoLA) Workshop, Helsinki, Finland, 27 July 1986

Summary. Two hundred and eighty-two alloantisera were submitted by 20 participating laboratories from 13 countries and tested against lymphocytes of 1298 cattle. The cell panel consisted of samples from 38 Bos taurus breeds, 11 Bos taurus crossbreeds, 4 Bos indicus breeds, 6 Bos taurus X Bos indicus , and a variety of other crossbred populations. Using a standardized lymphocytotoxicity test, all 17 previously identified BoLA specificities were confirmed. The workshop produced agreement on 16 new lymphocyte alloantigenic specificities. Three of the new specificities behaved as splits of previously identified BoLA specificities. Four of the new specificities behaved as alleles at the agreed BoLA-A locus. Seven new specificities are tentatively assigned to the BoLA-A locus but require further definition. Two new specificities may represent products of a second closely-linked BoLA locus.     

Genetic control of the quantitative variation of erythrocytic glyoxalase-1 (GLO-1) in mice

Quantitative genetic variation in the glyoxalase-1 content (QGlo-1) of red cells of mice is described. Its genetic control is shown to be exerted by either the Glo-1 locus or a closely linked gene to the left of H-2K. At least six alleles, designated QGlo-1 ^a through QGlo-1 ^f, can be found in different inbred strains of mice.This work was supported in part by Grants HL 0911 and AI 15413 of the National Institutes of Health and by a grant from the Sally and Alma Solomon Foundation.