EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15.
In mice, interleukin-7 (IL-7) and IL-15 are involved in T-cell homeostasis and the maintenance of immunologic memory. Here, we follow virus-induced responses in infectious mononucleosis (IM) patients from primary Epstein-Barr virus (EBV) infection into long-term virus carriage, monitoring IL-7 and IL-15 receptor (IL-R) expression by antibody staining and cytokine responsiveness by STAT5 phosphorylation and in vitro proliferation. Expression of IL-7Ralpha was lost from all CD8+ T cells, including EBV epitope-specific populations, during acute IM. Thereafter, expression recovered quickly on total CD8+ cells but slowly and incompletely on EBV-specific memory cells. Expression of IL-15Ralpha was also lost in acute IM and remained undetectable thereafter not just on EBV-specific CD8+ populations but on the whole peripheral T- and natural killer (NK)-cell pool. This deficit, correlating with defective IL-15 responsiveness in vitro, was consistently observed in patients up to 14 years after IM but not in patients after cytomegalovirus (CMV)-associated mononucleosis, or in healthy EBV carriers with no history of IM, or in EBV-naive individuals. By permanently scarring the immune system, symptomatic primary EBV infection provides a unique cohort of patients through which to study the effects of impaired IL-15 signaling on human lymphocyte functions in vitro and in vivo.
Cancer Research United Kingdom (CRUK) Institute for Cancer Studies and the Medical Research Council (MRC) Centre for Immune Regulation, University of Birmingham, Birmingham B15 2TT, United Kingdom.
Delphine
D
Sauce
Martin
M
Larsen
S John
SJ
Curnow
Alison M
AM
Leese
Paul A H
PA
Moss
Andrew D
AD
Hislop
Michael
M
Salmon
Alan B
AB
Rickinson
D000293:Adolescent; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002452:Cell Count; D002478:Cells, Cultured; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000821:virology; D006801:Humans; D007244:Infectious Mononucleosis / Q000276:immunology* / Q000821:virology; D019409:Interleukin-15 / Q000494:pharmacology / Q000502:physiology*; D053720:Interleukin-15 Receptor alpha Subunit / Q000378:metabolism*; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D013995:Time
D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit