RESUMO
Invariant natural killer T (iNKT)-cell development is controlled by many polymorphic genes present in commonly used mouse inbred strains. Development of type 1 diabetes (T1D) in NOD mice partly results from their production of fewer iNKT-cells compared with non-autoimmune-prone control strains, including ICR. We previously identified several iNKT-cell quantitative trait genetic loci co-localized with known mouse and human T1D regions in a (NOD × ICR)F2 cross. To further dissect the mechanisms underlying the impaired iNKT-cell compartment in NOD mice, we carried out a series of bone marrow transplantation as well as additional genetic mapping studies. We found that impaired iNKT-cell development in NOD mice was mainly due to the inability of their double-positive (DP) thymocytes to efficiently select this T-cell population. Interestingly, we observed higher levels of CD1d expression by NOD than by ICR DP thymocytes. The genetic control of the inverse relationship between the CD1d expression level on DP thymocytes and the frequency of thymic iNKT-cells was further mapped to a region on chromosome 13 between 60.12 and 70.59 Mb. The NOD allele was found to promote CD1d expression and suppress iNKT-cell development. Our results indicate that genetically controlled physiological variation of CD1d expression levels modulates iNKT-cell development.
Assuntos
Antígenos CD1d/genética , Cromossomos de Mamíferos , Regulação da Expressão Gênica , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Locos de Características Quantitativas , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Diferenciação Celular , Mapeamento Cromossômico , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos ICR , Camundongos Endogâmicos NOD , Modelos Animais , Células T Matadoras Naturais/citologia , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária , Timócitos/citologia , Timócitos/imunologia , Timócitos/metabolismoRESUMO
Reduced frequency of invariant natural killer T (iNKT) cells has been indicated as a contributing factor to type 1 diabetes (T1D) development in NOD mice. To further understand the genetic basis of the defect, we generated (NOD × ICR)F2 mice to map genes that control iNKT-cell development. We determined frequencies of thymic and splenic iNKT cells, as well as the ratio of CD4-positive and -negative subsets in the spleens of 209 F2 males. Quantitative trait loci (QTL) analysis revealed five loci that exceed the significant threshold for the frequency of thymic and/or splenic iNKT cells on Chromosomes (Chr) 1, 5, 6, 12 and 17. Three significant loci on Chr 1, 4 and 5 were found for the ratio of CD4-positive and -negative splenic iNKT cells. Comparisons with previously known mouse T1D susceptibility (Idd) loci revealed two significant QTL peak locations, respectively, mapped to Idd regions on Chr 4 and 6. The peak marker location of the significant Chr 12 iNKT QTL maps to within 0.5 Mb of a syntenic human T1D locus. Collectively, our results reveal several novel loci controlling iNKT-cell development and provide additional information for future T1D genetic studies.
Assuntos
Diabetes Mellitus Tipo 1/genética , Ligação Genética , Loci Gênicos , Células T Matadoras Naturais/citologia , Locos de Características Quantitativas , Animais , Cromossomos de Mamíferos/genética , Diabetes Mellitus Tipo 1/imunologia , Predisposição Genética para Doença , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Endogâmicos NOD , Baço/citologia , Subpopulações de Linfócitos T/citologia , Timo/citologiaRESUMO
The 2,272,351-base pair genome of Neisseria meningitidis strain MC58 (serogroup B), a causative agent of meningitis and septicemia, contains 2158 predicted coding regions, 1158 (53.7%) of which were assigned a biological role. Three major islands of horizontal DNA transfer were identified; two of these contain genes encoding proteins involved in pathogenicity, and the third island contains coding sequences only for hypothetical proteins. Insights into the commensal and virulence behavior of N. meningitidis can be gleaned from the genome, in which sequences for structural proteins of the pilus are clustered and several coding regions unique to serogroup B capsular polysaccharide synthesis can be identified. Finally, N. meningitidis contains more genes that undergo phase variation than any pathogen studied to date, a mechanism that controls their expression and contributes to the evasion of the host immune system.