Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A

Abbe N. Vallejo, Joshua J. Michel, Laurie K. Bale, Bonnie H. Lemster, Lisa Borghesi, Cheryl A Conover

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that controls the tissue availability of insulin-like growth factor (IGF). Homozygous deletion of PAPPA in mice leads to lifespan extension. Since immune function is an important determinant of individual fitness, we examined the natural immune ecology of PAPPA-/- mice and their wild-type littermates reared under specific pathogen-free condition with aging. Whereas wild-type mice exhibit classic age-dependent thymic atrophy, 18-month-old PAPPA-/- mice maintain discrete thymic cortex and medulla densely populated by CD4+CD8+ thymocytes that are capable of differentiating into singlepositive CD4 and CD8 T cells. Old PAPPA-/- mice have high levels of T cell receptor excision circles, and have bone marrows enriched for subsets of thymus-seeding progenitors. PAPPA-/- mice have an overall larger pool of naive T cells, and also exhibit an age-dependent accumulation of CD44+CD43+ memory T cells similar to wild-type mice. However, CD43+ T cell subsets of old PAPPA -/- mice have significantly lower prevalence of 1B11 and S7, glycosylation isoforms known to inhibit T cell activation with normal aging. In bioassays of cell activation, splenic T cells of old PAPPA-/- mice have high levels of activation antigens and cytokine production, and also elicit Ig production by autologous B cells at levels equivalent to young wild-type mice. These data suggest an IGF-immune axis of healthy longevity. Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune homeostasis during postnatal development and aging.

Original languageEnglish (US)
Pages (from-to)11252-11257
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number27
DOIs
StatePublished - Jul 7 2009

Fingerprint

Pregnancy-Associated Plasma Protein-A
Atrophy
T-Lymphocytes
Somatomedins
Thymus Gland
ethyl-2-methylthio-4-methyl-5-pyrimidine carboxylate
Specific Pathogen-Free Organisms
T-Lymphocyte Subsets
Metalloproteases
Thymocytes
T-Cell Antigen Receptor
Ecology
Glycosylation
Biological Assay
Protein Isoforms
Homeostasis
B-Lymphocytes
Bone Marrow

Keywords

  • Aging
  • Insulin-like growth factor
  • T cells
  • Thymus

ASJC Scopus subject areas

  • General

Cite this

Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A. / Vallejo, Abbe N.; Michel, Joshua J.; Bale, Laurie K.; Lemster, Bonnie H.; Borghesi, Lisa; Conover, Cheryl A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 27, 07.07.2009, p. 11252-11257.

Research output: Contribution to journalArticle

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abstract = "Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that controls the tissue availability of insulin-like growth factor (IGF). Homozygous deletion of PAPPA in mice leads to lifespan extension. Since immune function is an important determinant of individual fitness, we examined the natural immune ecology of PAPPA-/- mice and their wild-type littermates reared under specific pathogen-free condition with aging. Whereas wild-type mice exhibit classic age-dependent thymic atrophy, 18-month-old PAPPA-/- mice maintain discrete thymic cortex and medulla densely populated by CD4+CD8+ thymocytes that are capable of differentiating into singlepositive CD4 and CD8 T cells. Old PAPPA-/- mice have high levels of T cell receptor excision circles, and have bone marrows enriched for subsets of thymus-seeding progenitors. PAPPA-/- mice have an overall larger pool of naive T cells, and also exhibit an age-dependent accumulation of CD44+CD43+ memory T cells similar to wild-type mice. However, CD43+ T cell subsets of old PAPPA -/- mice have significantly lower prevalence of 1B11 and S7, glycosylation isoforms known to inhibit T cell activation with normal aging. In bioassays of cell activation, splenic T cells of old PAPPA-/- mice have high levels of activation antigens and cytokine production, and also elicit Ig production by autologous B cells at levels equivalent to young wild-type mice. These data suggest an IGF-immune axis of healthy longevity. Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune homeostasis during postnatal development and aging.",
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