title: T cells Exhibit Reduced Signal Transducer and Activator of Transcription 5 Phosphorylation and Upregulated Coinhibitory Molecule Expression After Kidney Transplantation.
abstract: BACKGROUND
  T-cell depletion therapy is associated with diminished interleukin (IL)-7/IL-15-dependent homeostatic proliferation resulting in incomplete T-cell repopulation. Furthermore, it is associated with impaired T-cell functions. We hypothesized that this is the result of impaired cytokine responsiveness of T cells, through affected signal transducer and activator of transcription (STAT)5 phosphorylation and upregulation of coinhibitory molecules.
  
  
  METHODS
  Patients were treated with T cell-depleting rabbit antithymocyte globulin (rATG) (6 mg/kg, n = 17) or nondepleting, anti-CD25 antibody (basiliximab, 2 × 40 mg, n = 25) induction therapy, in combination with tacrolimus, mycophenolate mofetil, and steroids. Before and the first year after transplantation, IL-7 and IL-2 induced STAT5 phosphorylation, and the expression of the coinhibitory molecules programmed cell death protein 1 (PD-1), T cell immunoglobulin mucin-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), cluster of differentiation (CD) 160, and CD244 was measured by flow cytometry.
  
  
  RESULTS
  The first year after rATG, CD4+, and CD8+ T cells were affected in their IL-7-dependent phosphorylation of STAT5 (pSTAT5) which was most outspoken in the CD8+ memory population. The capacity of CD4+ and CD8+ T cells to pSTAT5 in response to IL-2 decreased after both rATG and basiliximab therapy. After kidney transplantation, the percentage of TIM-3+, PD-1+, and CD160+CD4+ T cells and the percentage of CD160+ and CD244+CD8+ T cells increased, with no differences in expression between rATG- and basiliximab-treated patients. The decrease in pSTAT5 capacity CD8+ T cells and the increase in coinhibitory molecules were correlated.
  
  
  CONCLUSIONS
  We show that memory T cells in kidney transplant patients, in particular after rATG treatment, have decreased cytokine responsiveness by impaired phosphorylation of STAT5 and have increased expression of coinhibitory molecules, processes which were correlated in CD8+ T cells.
authors.affiliation: 1 Department of Internal Medicine, Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. 2 Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Anne P
authors.initials: AP
authors.lastname: Bouvy
authors.forename: Mariska
authors.initials: M
authors.lastname: Klepper
authors.forename: Marcia M L
authors.initials: MM
authors.lastname: Kho
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Ijzermans
authors.forename: Michiel G H
authors.initials: MG
authors.lastname: Betjes
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D000961:Antilymphocyte Serum / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000378:metabolism; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000276:immunology / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071176:Signaling Lymphocytic Activation Molecule Family; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D000961:Antilymphocyte Serum; C114505:CD160 protein, human; C084093:CD244 protein, human; D060908:CTLA-4 Antigen; D061025:Costimulatory and Inhibitory T-Cell Receptors; D058851:GPI-Linked Proteins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D050799:STAT5 Transcription Factor; D000071176:Signaling Lymphocytic Activation Molecule Family; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human