title: Tuning of T cell clone size and activation threshold by control of CD25 expression through mitogen-activated protein kinase pathways.
abstract: BACKGROUND
  Following T cell receptor (TcR) engagement, CD25 expression is upregulated by T cells and controls their proliferation. It is not known how CD25 expression levels differentially influence T helper (Th) 1 and Th2 cell physiology.
  
  
  METHODS
  CD25 upregulation, and other T cell functions, were studied in human Th1 and Th2 clones following stimulation with various stimuli. The effects of pharmacological substances were then evaluated to identify the signaling pathways controlling CD25 upregulation.
  
  
  RESULTS
  Upon TcR engagement, one Th2 clone was induced to express substantially more CD25 than a Th1 clone, although both clones downregulated CD3 with similar dose responses. It was also found that the amount of antigen needed to elicit proliferation and cytokine production was considerably lowered in the presence of interleukin-2 (IL-2) for the Th2 cells, while for the Th1 cells the threshold of activation was not modified by the presence of IL-2. It was then shown that PP2 and cyclosporin A strongly inhibited CD25 expression in both clones, while wortmannin and Ro-31-8220 had more limited effects. In contrast, mitogen-activated protein kinase (MAPK) inhibitors had strikingly different effects on CD25, blocking its expression in the Th2 cells, while augmenting it, or leaving it unaffected, in the Th1 cells.
  
  
  CONCLUSIONS
  These unexpected observations suggested that in some T cells TcR-mediated activation of the MAPK pathways may inhibit CD25 expression rather than promoting it. Absence of this negative control mechanism may endow Th2 cells with a growth advantage over Th1 cells and their effector functions may be elicited at lower antigen doses.
authors.affiliation: Pfizer Global Research and Development, Fresnes, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Bitegye
authors.forename: Sigrid
authors.initials: S
authors.lastname: Hannier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Guérif
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valitutti
authors.forename: Stéphane
authors.initials: S
authors.lastname: Demotz
mesh_terms: D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002453:Cell Cycle / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium