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. MATERIALS AND 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.
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. MATERIALS AND 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: Nynke M Kannegieter; Dennis A Hesselink; Marjolein Dieterich; Gretchen N de Graav; Rens Kraaijeveld; Carla C Baan Journal: Sci Rep Date: 2017-11-09 Impact factor: 4.379
Authors: Marieke van der Zwan; Marian C Clahsen-Van Groningen; Joke I Roodnat; Anne P Bouvy; Casper L Slachmuylders; Willem Weimar; Carla C Baan; Dennis A Hesselink; Marcia M L Kho Journal: Ann Transplant Date: 2018-08-17 Impact factor: 1.530
Authors: Netonia Marshall; Keino Hutchinson; Thomas U Marron; Mark Aleynick; Linda Hammerich; Ranjan Upadhyay; Judit Svensson-Arvelund; Brian D Brown; Miriam Merad; Joshua D Brody Journal: Cancer Discov Date: 2019-08-02 Impact factor: 39.397
Authors: Anne P Bouvy; Mariska Klepper; Michiel G H Betjes; Willem Weimar; Dennis A Hesselink; Carla C Baan Journal: Transplant Direct Date: 2016-05-25