CD4+ and CD8+T-cell reactions against leukemia-associated- or minor-histocompatibility-antigens in AML-patients after allogeneic SCT

Brigitte Steger, Slavoljub Milosevic, Georg Doessinger, Susanne Reuther, Anja Liepert, Marion Braeu, Julia Schick, Valentin Vogt, Friedhelm Schuster, Tanja Kroell, Dirk H. Busch, Arndt Borkhardt, Hans Jochem Kolb, Johanna Tischer, Raymund Buhmann, Helga Schmetzer

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

T-cells play an important role in the remission-maintenance in AML-patients (pts) after SCT, however the role of LAA- (WT1, PR1, PRAME) or minor-histocompatibility (mHag, HA1) antigen-specific CD4+ and CD8+T-cells is not defined.A LAA/HA1-peptide/protein stimulation, cloning and monitoring strategy for specific CD8+/CD4+T-cells in AML-pts after SCT is given.Our results show that (1) LAA-peptide-specific CD8+T-cells are detectable in every AML-pt after SCT. CD8+T-cells, recognizing two different antigens detectable in 5 of 7 cases correlate with long-lasting remissions. Clonal TCR-Vβ-restriction exemplarily proven by spectratyping in PRAME-specific CD8+T-cells; high PRAME-peptide-reactivity was CD4+-associated, as shown by IFN-γ-release. (2) Two types of antigen-presenting cells (APCs) were tested for presentation of LAA/HA1-proteins to CD4+T-cells: miniEBV-transduced lymphoblastoid cells (B-cell-source) and CD4-depleted MNC (source for B-cell/monocyte/DC). We provide a refined cloning-system for proliferating, CD40L+CD4+T-cells after LAA/HA1-stimulation. CD4+T-cells produced cytokines (GM-CSF, IFN-γ) upon exposure to LAA/HA1-stimulation until after at least 7 restimulations and demonstrated cytotoxic activity against naive blasts, but not fibroblasts. Antileukemic activity of unstimulated, stimulated or cloned CD4+T-cells correlated with defined T-cell-subtypes and the clinical course of the disease.In conclusion we provide immunological tools to enrich and monitor LAA/HA1-CD4+- and CD8+T-cells in AML-pts after SCT and generate data with relevant prognostic value. We were able to demonstrate the presence of LAA-peptide-specific CD8+T-cell clones in AML-pts after SCT. In addition, we were also able to enrich specific antileukemic reactive CD4+T-cells without GvH-reactivity upon repeated LAA/HA1-protein stimulation and limiting dilution cloning.

Original languageEnglish
Pages (from-to)247-260
Number of pages14
JournalImmunobiology
Volume219
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • Acute myeloid leukemia
  • CD4/CD8 T-cells
  • Dendritic cells
  • Immunophenotyping
  • Minor antigens
  • Multimer
  • TAA

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