Defective T-helper cell function after T-cell-depleting therapy affecting naive and memory populations.
Impaired T-cell function after T-cell- depleting (TCD) therapy has been hypothesized to be related to a transient predominance of extrathymically expanding memory T cells. To test whether after TCD therapy the naive T-helper cell population is functionally intact, the in vitro immune response of CD4(+)CD45RA(+) (naive) and of CD4(+)CD45RA(-) (memory) cells to polyclonal mitogens (immobilized anti-CD3, phytohemagglutinin) was analyzed by flow cytometry in 22 pediatric patients after high-dose chemotherapy (including 5 after autologous and 5 after allogeneic stem cell support). At 1 to 3 months after TCD therapy, patient samples showing decreased lymphoproliferative responses also showed a reduced induction of the early activation marker CD69 by CD4(+) T cells from 4 to 72 hours after stimulation even when supplemented with exogenous interleukin-2. This defect affected CD4(+)CD45RA(-) cells, but, strikingly, also CD4(+)CD45RA(+) cells, including samples in which CD4(+)CD45RA(+) cells were more than 90/microL, thus indicating ongoing thymopoiesis. Histogram analyses showed the median peak channel of CD69 in control CD4(+)CD45RA(+) cells rising 98-fold (median) but only 28-fold in patient cells (P <.0001). Apoptosis as detected by annexin V staining was increased in resting patient CD4(+) T cells (25% versus 6%) and also affected CD4(+)CD45RA(+) cells (12% versus 5%, P <.01). When peripheral blood mononuclear cells (PBMCs) were enriched for T cells, stimulatory responses of CD4(+) cells and of CD4(+)CD45RA(+) cells markedly improved. Thus, after TCD therapy suppressor factors contained in the non-T-cell fraction of PBMCs may affect T-helper cells irrespective of their naive or memory phenotype thus extending T-cell dysfunction to the presumably thymus-dependently regenerated T cells.
Heitger
Andreas
A
University Children's Hospital Innsbruck; Department of Urology, University Innsbruck, Austria. andreas.heitger@uibk.ac.at
Winklehner
Patricia
P
Obexer
Petra
P
Eder
Johannes
J
Zelle-Rieser
Claudia
C
Kropshofer
Gabriele
G
Thurnher
Martin
M
Holter
Wolfgang
W
D000293:Adolescent; D017304:Annexin A5 / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002462:Cell Membrane / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007156:Immunologic Memory; D007223:Infant; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens / Q000276:immunology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D013997:Time Factors; D014182:Transplantation, Autologous / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology; D000099192:CD69 Antigens
D017304:Annexin A5; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens; D000099192:CD69 Antigens