Defective T-helper cell function after T-cell-depleting therapy affecting naive and memory populations

Blood. 2002 Jun 1;99(11):4053-62. doi: 10.1182/blood.v99.11.4053.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Annexin A5 / immunology
  • Antigens, CD / immunology
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • Binding Sites
  • CD4 Antigens / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Membrane / immunology
  • Child
  • Child, Preschool
  • Female
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Immunologic Memory*
  • Infant
  • Lectins, C-Type
  • Leukocyte Common Antigens / immunology
  • Lymphocyte Activation
  • Lymphocyte Depletion*
  • Male
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Time Factors
  • Transplantation, Autologous / immunology
  • Transplantation, Homologous / immunology

Substances

  • Annexin A5
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD4 Antigens
  • CD69 antigen
  • Lectins, C-Type
  • Leukocyte Common Antigens