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Immunosenescence in Dendritic Cells: Defects in TLR-Induced Cytokine Production and CD80/86 Expression

This study explores immunosenescence in dendritic cells (DCs) and its impact on vaccine response to influenza. The findings reveal age-associated defects in TLR-induced cytokine production and CD80/86 expression in DCs, suggesting potential markers for immunosenescence. The study also highlights a decrease in PRAT4A protein expression in older adults, indicating a possible role in age-related immune dysregulation. Future plans include qPCR analysis, gene cloning, and confocal microscopy to further investigate the mechanisms underlying these age-associated alterations in DCs.

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Immunosenescence in Dendritic Cells: Defects in TLR-Induced Cytokine Production and CD80/86 Expression

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  1. BROOKDALE RETREAT 2011 Alexander Panda 2010 Brookdale Leadership in Aging Fellow Yale University School of Medicine June 08, 2011

  2. Where we started: • Evidence for immunosenescence in DCs: a more generalized defect in TLR-induced cytokine production than we observed previously in monocytes from older subject • TLR-induced cytokine production in DCs can predict vaccine response to influenza (in contrast to our results in monocytes) • Decreased surface and intracellular TLR expression arises from both transcriptional and post-transcriptional mechanisms

  3. Age-associated alterations in Toll-like receptor (TLR)–induced CD80/86 expression in mDCs in older, compared to young adults. Age-associated defects (n=104) in CD80 expression in mDCs following stimulation with indicated TLR ligands.

  4. Age-associated alterations in Toll-like receptor (TLR)–induced CD80/86 expression in mDCs and pDCs in older, compared to young adults TLR-induced cytokine production in DCs can predict vaccine response to influenza Identification a potential new marker for immunosenescence in young adults: a CD86 high population on mDCs, only present in young adults

  5. Young Young Old Old Unstimulated control Unstimulated control Old Young Young Old Stimulated Stimulated When gating on mDCs a CD86 high population is seen in young individuals. This CD86 high population was not seen in old individuals.

  6. Data in Monocytes: • post-translational defect in TLR1 surface expression without a defect in TLR1 transcription • Role of chaperones associated with TLR expression • PRAT4A

  7. PRAT4A Protein Expression is Decreased in Older Adults Older (n=49) Young (n=48) * p< 0.0001

  8. Detection of intracellular PRAT4A in mDCs of young (n=30) and old (n=30) individuals by FACS analysis % gated mDCs Age-associated decrease in PRAT4A protein expression. Shown are percent positive mDCs (compared with isotype control). Values indicate the mean ± SEM. (p < 0.001, t-test)

  9. Detection of intracellular PRAT4A in pDCs of young (n=30) and old (n=30) individuals by FACS analysis % gated pDCs Age-associated decrease in PRAT4A protein expression. Shown are percent positive pDCs (compared with isotype control). Values indicate the mean ± SEM. (p < 0.001, t-test)

  10. Plans: • PRAT4A expression analysis by real-time quantitative-PCR (qPCR) • Cloning and sequencing of PRAT4A of PRAT4A gene in old and young individuals to account for potential splicing variants • Cloning of PRAT4A gene and transfection of bead isolated monocytes to evaluate the potential for rescuing TLR responses • Confocal Microscopy to evaluate age associated differences in the distribution and/or redistribution of PRAT4A in bead isolated monocytes

  11. Feng Qian Lin Zhang Donna Carrano Subhasis Mohanty David van Duin Al Shaw Ruth Montgomery Steve Malawista Erol Fikrig Ruslan Medzhitov Takuma Shibata (Tokyo University) Kensuke Miyake (Tokyo University) Fran Newman (Saint Louis University) Robert Belshe (Saint Louis University) Program on Aging: Mary Tinetti Heather Allore Sandra Ginter Joanne McGloin Virginia Towle Peter Charpentier Study Nurses Yale Health Plan: Ravi Durvasula Michael Rigsby Claude D. Pepper Older Americans Independence Center Hartford Foundation Center of Excellence In Aging NIH/NIAID Acknowledgements

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