Disease relevance of Tap1

• In this study, we demonstrate that, similar to lymphoma cell lines with mutations in Tap-1 or Tap-2, the reduced expression of class I molecules on the surface of lymphocytes from diabetes-prone female NOD mice was normalized by incubation at low temperatures or by exposure to class I allele-specific peptides [1].
• Superinfection with VV-mtp1 and VV-mtp2 rendered both cell lines, after infection with either VV-Kk and VV-Kd, susceptible to lysis by either Kk- or Kd-restricted VV-immune Tc cells [2].

High impact information on Tap1

• These data indicate that both MHC-linked transporter genes are probably required for class I antigen processing, and that the functional transporter in this pathway may consist of a Ham-1/Ham-2 heterodimer [3].
• Evidence for such a function has come from the rescue of class I surface expression by a cloned copy of the human homologue of Ham-1, PSF-1, in a human cell line that is defective in antigen processing [3].
• Like the corresponding genes RING4, HAM1 and mtp1, PSF is related to the multidrug-resistance family of transporters and may be a peptide pump, as translocation of peptides across membranes must occur independently of the secretory pathway [4].
• Introduction of transgenes encoding either NP34 or NP68 along with an endoplasmic reticulum signal sequence enabled Tap-1-independent expression of each peptide in these mice [5].
• In this study we analyzed the effects of a transgene encoding an antagonist peptide (influenza NP34) that is presented by H-2Db in a Tap-1-independent fashion in mice expressing the influenza NP68-specific TCR F5 [6].

Biological context of Tap1

• Northern blot revealed reduced amounts of Tap1 and Lmp2 mRNA in NOD mice, and 5'-rapid amplification of cDNA ends revealed the loss of a transcription start site of Lmp2 in these animals [7].
• The murine major histocompatibility complex (MHC) contains two genes (Ham-1 and Ham-2) that encode members of a super-family of ATP-dependent transport proteins [3].
• Then we determined the PED phenotype of both Tap 1 knockout mouse embryos and control mouse embryos [8].
• We have determined the nucleotide sequence of the region encompassing the whole Lmp-2 gene and three exons of Tap-1, which spans 8 kb in the mouse genome [9].
• Tap-1 genes of NON and C57BL/6 mice were equally sensitive to up-regulation by IFN-gamma [10].

Anatomical context of Tap1

• To test whether this effect depended on an intact immune system, we generated heteroplasmic mice missing functional copies of Tap1, beta2m or Rag1 to impair presentation or recognition of mtDNA-encoded peptides [11].
• Lmp2 and Tap1 are genes located in the MHC class II region, and they encode proteins participating in the generation and transport of endogenous peptides for T cell education [7].
• In macrophages from STAT-1 knockout mice, neither LPS nor TNF-alpha induced the expression of Tap1 or Lmp2 [12].
• The Tap-1 and Tap-2 genes presumably encode a heterodimeric protein complex responsible for transporting endogenous immunogenic peptides to the lumen of the endoplasmic reticulum [13].
• NOD mice possess a rare Tap-1 allele (Tap-1b); this is associated with reduced Tap-1 mRNA abundance in lymphocytes from diabetes-prone females and decreased conformationally correct class I molecules on the cell surface [1].

Regulatory relationships of Tap1

• These results show that LPS and TNF-alpha regulate the induction of Tap1 and Lmp2 through STAT1, but use distinct areas of the promoter [12].
• Mice with a homozygous deletion in their Tap-1 gene (-/- mice) express very low levels of cell membrane major histocompatibility complex class I molecules and have < 1% peripheral CD8+ T cells [14].

Other interactions of Tap1

• By making deletions of the promoter, we determined that only the proximal GAS box is required for LPS induction of Tap1 and Lmp2 [12].
• The shared promoter contains several areas that can be controlled by STAT-1, such as the proximal and distal IFN-gamma activation site (GAS) boxes in the direction of the Tap1 gene [12].
• Thus, the Tap-1 3' end gene region and the Lmp-7 initial translation codon are separated by an 1182 nucleotide region which contains a TATA-box, a cAMP regulatory element, two SP1 sites, and two G-C-rich regions [15].
• To distinguish further between epitopes II and III, Y-2 and Y-3 CTL clones were reacted with SV40-transformed cells bearing mutations in the major histocompatibility complex class I antigen [16].

Analytical, diagnostic and therapeutic context of Tap1

• To avoid amplifying other members of the transporter family, we used a gel-purified 1670-bp Tap-1 PCR "long product" as template for nested PCR [10].
• We examined Tap-1 and Tap-2 mRNA levels in NOD/Smrf mice using a reverse transcriptase-polymerase chain reaction method that detects > or = 25% changes in mRNA [17].
• MHC class I synthesis was determined by immunoprecipitation of the cell lysates with an anti-Kb monoclonal antibody, Y3 [18].

References