Cytokines and impaired CD8+ CTL activity among elderly persons and the enhancing effect of IL-12.
We have previously demonstrated that about 70% of elderly persons exhibit deficient cytotoxic T lymphocyte (CD8+ CTL) responses against influenza viruses when compared to young persons. Since IFN-gamma, a Th1 cytokine and IL-4, a Th2 cytokine, stimulate and inhibit CD8+ CTL responses respectively, their role(s) in the age-related CTL deficiency was investigated. Lymphocytes from young adults (34 +/- 5 years old) and elderly subjects (71 +/- 1 years old) were stimulated in vitro with influenza A/H3N2, A/H1N1 or influenza B virus for 6-7 days. The CD8+ CTL activity against virus-infected autologous target cells was significantly lower among the elderly than the young subjects (P < 0.01). Following stimulation with influenza virus, IL-4 production in both age groups was similar on day 3 but significantly higher among elderly persons on day 6 (P < 0.05). In contrast, T cells from the elderly produced significantly lower IFN-gamma than did those from young persons on both days (P < 0.05). Treatment of T cells from young and elderly adults with recombinant human IL-12, a pivotal cytokine that stimulates Th1 cytokines, resulted in enhancement of CD8+ CTL activity and IFN-gamma production in a dose dependent manner (P < 0.01). IL-12-dependent enhancement of CTL activity was not always abrogated by anti-IFN-gamma antibody treatment. These results suggest that deficient influenza virus-specific CTL activity among the elderly is attributable to a Th1 to Th2 cytokine production switch. Immunotherapy with IL-12 could represent a useful approach to correct the CD8+ CTL deficiency and cytokine imbalance among elderly humans.
Mbawuike
I N
IN
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. mbawuike@bcm.tmc.edu
Acuna
C L
CL
Walz
K C
KC
Atmar
R L
RL
Greenberg
S B
SB
Couch
R B
RB
D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology* / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008297:Male; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*
D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma