Contribution of naïve and memory T-cell populations to the human alloimmune response

Am J Transplant. 2009 Sep;9(9):2057-66. doi: 10.1111/j.1600-6143.2009.02742.x. Epub 2009 Jul 16.

Abstract

T-cell alloimmunity plays a dominant role in allograft rejection. The precise contribution of naïve and memory T cells to this response however remains unclear. To address this question, we established an ex vivo flow-cytometric assay that simultaneously measures proliferation, precursor frequency and effector molecule (IFNgamma, granzyme B/perforin) production of alloreactive T cells. By applying this assay to peripheral blood mononuclear cells from healthy volunteers, we demonstrate that the CD4+ and CD8+ populations mount similar proliferative responses and contain comparable frequencies of alloreactive precursors. Effector molecule expression, however, was significantly higher among CD8+ T cells. Analysis of sorted naïve and memory T cells showed that alloreactive precursors were equally present in both populations. The CD8+ effector and terminally differentiated effector memory subsets contained the highest proportion of granzyme B/perforin after allostimulation, suggesting that these cells present a significant threat to transplanted organs. Finally, we demonstrate that virus-specific lymphocytes contribute significantly to the alloresponse in certain responder-stimulator HLA combinations, underscoring the importance of T-cell cross-reactivity in alloimmunity. These results provide a quantitative assessment of the roles of naïve and memory T-cell subsets in the normal human alloimmune response and establish a platform for measuring T-cell alloreactivity pre- and posttransplantation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Proliferation
  • Female
  • Flow Cytometry / methods
  • Granzymes / pharmacology
  • HLA Antigens / chemistry
  • Humans
  • Immunologic Memory / immunology
  • Interferon-gamma / metabolism
  • Male
  • Perforin / metabolism
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes / cytology*

Substances

  • HLA Antigens
  • Perforin
  • Interferon-gamma
  • Granzymes