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.
Sauce
Delphine
D
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.
Larsen
Martin
M
Curnow
S John
SJ
Leese
Alison M
AM
Moss
Paul A H
PA
Hislop
Andrew D
AD
Salmon
Michael
M
Rickinson
Alan B
AB
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