Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function

Blood. 2012 Mar 15;119(11):2665-74. doi: 10.1182/blood-2011-10-386995. Epub 2011 Dec 16.

Abstract

During mouse cytomegalovirus (CMV) infection, a population of Ly49H(+) natural killer (NK) cells expands and is responsible for disease clearance through the induction of a "memory NK-cell response." Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C(+) NK cells expanded and were potent producers of IFNγ. NKG2C(+) NK cells predominately expressed killer cell immunoglobulin-like receptor, and self-killer cell immunoglobulin-like receptors were required for robust IFNγ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56(dim) NK cells. Strikingly, increased frequencies of NKG2C(+) NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C(+) NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFNγ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFNγ, T-bet, and IL-15Rα mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation.

Publication types

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

MeSH terms

  • Biomarkers / metabolism
  • Blotting, Western
  • CD57 Antigens / metabolism*
  • Cohort Studies
  • Cytomegalovirus / immunology*
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / therapy
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • NK Cell Lectin-Like Receptor Subfamily C / immunology*
  • NK Cell Lectin-Like Receptor Subfamily C / metabolism*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, KIR / genetics
  • Receptors, KIR / metabolism
  • Receptors, KIR2DL2 / genetics
  • Receptors, KIR2DL2 / metabolism
  • Receptors, KIR2DL3 / genetics
  • Receptors, KIR2DL3 / metabolism
  • Transplantation, Homologous
  • Virus Replication

Substances

  • Biomarkers
  • CD57 Antigens
  • KIR2DS2 protein, human
  • NK Cell Lectin-Like Receptor Subfamily C
  • RNA, Messenger
  • Receptors, KIR
  • Receptors, KIR2DL2
  • Receptors, KIR2DL3
  • Interferon-gamma