CD4 T cell differentiation into multiple T helper (Th) cell lineages is critical for optimal adaptive immune responses. This report identifies an intrinsic mechanism by which programmed death-1 receptor (PD-1) signaling imparted regulatory phenotype to Foxp3 Th1 cells (denoted as TbetiTreg cells) and inducible regulatory T (iTreg) cells. TbetiTreg cells prevented inflammation in murine models of experimental colitis and experimental graft versus host disease (GvHD). Programmed death ligand-1 (PDL-1) binding to PD-1 imparted regulatory function to TbetiTreg cells and iTreg cells by specifically downregulating endo-lysosomal protease asparaginyl endopeptidase (AEP). AEP regulated Foxp3 stability and blocking AEP imparted regulatory function in TbetiTreg cells. Also, Aep iTreg cells significantly inhibited GvHD and maintained Foxp3 expression. PD-1-mediated Foxp3 maintenance in Tbet Th1 cells occurred both in tumor infiltrating lymphocytes (TILs) and during chronic viral infection. Collectively, this report has identified an intrinsic function for PD-1 in maintaining Foxp3 through proteolytic pathway.

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The art/trs transactivator protein of human immunodeficiency virus (HIV) was expressed in mammalian cells as a 19-kilodalton protein that was immunoreactive with sera from HIV-infected patients. Separate plasmids encoding the art/trs protein, the tat protein, or the envelope glycoprotein gp120 were used to demonstrate that both art/trs and tat are absolutely required for the synthesis of gp120 from its cognate messenger RNA. In addition, both the tat and art/trs proteins influence the level of envelope RNA. The results suggest that art/trs and tat may be ideal targets for potential anti-HIV agents in AIDS therapy.

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We have isolated a full-length cDNA clone (thymic stromal origin (TSO)-1C12) from a SCID thymus library using a probe from a PCR-based subtractive library enriched for sequences from fetal thymic stromal cells. TSO-1C12 mRNA is expressed mainly in the thymic cortex and is highly enriched in SCID thymus. Expression per cell is highest during fetal thymus development and decreases after day 16. Antipeptide Abs immunoprecipitated a hydrophobic, plasma membrane glycoprotein (thymic stromal cotransporter, TSCOT) whose translated sequence has weak homology to bacterial antiporters and mammalian cation cotransporters with 12 transmembrane domains. TSCOT represents a new member of this superfamily that is highly expressed in thymic cortical epithelial cells.