title: Downregulation of inhibitory SRC homology 2 domain-containing phosphatase-1 (SHP-1) leads to recovery of T cell responses in elderly.
abstract: BACKGROUND
  Immune responses are generally impaired in aged mammals. T cells have been extensively studied in this context due to the initial discovery of their reduced proliferative capacity with aging. The decreased responses involve altered signaling events associated with the early steps of T cell activation. The underlying causes of these changes are not fully understood but point to alterations in assembly of the machinery for T cell activation. Here, we have tested the hypothesis that the T cell pool in elderly subjects displayed reduced functional capacities due to altered negative feedback mechanisms that participate in the regulation of the early steps of T cell activation. Such conditions tip the immune balance in favor of altered T cell activation and a related decreased response in aging.
  
  
  RESULTS
  We present evidence that the tyrosine phosphatase SHP-1, a key regulator of T cell signal transduction machinery is, at least in part, responsible for the impaired T cell activation in aging. We used tyrosine-specific mAbs and Western blot analysis to show that a deregulation of the Csk/PAG loop in activated T cells from elderly individuals favored the inactive form of tyrosine-phosphorylated Lck (Y505). Confocal microscopy analysis revealed that the dynamic movements of these regulatory proteins in lipid raft microdomains was altered in T cells of aged individuals. Enzymic assays showed that SHP-1 activity was upregulated in T cells of aged donors, in contrast to young subjects. Pharmacological inhibition of SHP-1 resulted in recovery of TCR/CD28-dependent lymphocyte proliferation and IL-2 production of aged individuals to levels approaching those of young donors. Significant differences in the active (Y394) and inactive (Y505) phosphorylation sites of Lck in response to T cell activation were observed in elderly donors as compared to young subjects, independently of CD45 isoform expression.
  
  
  CONCLUSIONS
  Our data suggest that the role of SHP-1 in T cell activation extends to its increased effect in negative feedback in aging. Modulation of SHP-1 activity could be a target to restore altered T cell functions in aging. These observations could have far reaching consequences for improvement of immunosenescence and its clinical consequences such as infections, altered response to vaccination.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Le Page
authors.forename: Carl
authors.initials: C
authors.lastname: Fortin
authors.forename: Hugo
authors.initials: H
authors.lastname: Garneau
authors.forename: Nancy
authors.initials: N
authors.lastname: Allard
authors.forename: Krassimira
authors.initials: K
authors.lastname: Tsvetkova
authors.forename: Crystal Tze Ying
authors.initials: CT
authors.lastname: Tan
authors.forename: Anis
authors.initials: A
authors.lastname: Larbi
authors.forename: Gilles
authors.initials: G
authors.lastname: Dupuis
authors.affiliation: Research Center on Aging, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 1036 rue Belvedere sud, Sherbrooke, J1H 4C4, Quebec, Canada. Tamas.Fulop@USherbrooke.ca.
authors.forename: Tamas
authors.initials: T
authors.lastname: Fülöp
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D021962:Membrane Microdomains / Q000378:metabolism; D009154:Mutation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism
chemical_list: C516587:2-amino-5H-pyrido(3',2';5,6)thiopyrano(4,3-d)pyrimidine; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D011743:Pyrimidines; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6