Significance of Calcium Signaling for Aging in Lymphocytes

• Applicant: Dr. Annette Johanna Lis
• Subject Area: Pharmacology ; Biophysics ; Immunology
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 226382080

• Final Report Year: 2017

Final Report Abstract

In the last years, we performed comprehensive assessments of the molecular repertoire governing Ca2+ signals in CD8+ T cells and investigated the influence of varying [Ca2+]ext on the main function of these cells, the lysis of target cells. Taken together, we found out that two mechanisms contribute to the overall reduction in Ca2+ signals of CD8+ T cells of elderly mice: 1) Reduced Ca2+ currents through Orai channels due to decreased expressions of STIMs and Orais. 2) A faster extrusion of Ca2+ owing to an increased expression of PMCA4. The reduced Ca2+ signals correlated with a resistance of the cytotoxic efficiency of CD8+ T cells to varying free [Ca2+]ext with age. In summary, reduced STIM/Orai expression and increased Ca2+ clearing rates following enhanced PMCA4 expression contribute to reduced Ca2+ signals in CD8+ T cells of elderly mice. These changes are apparently relevant to immune function as they reduce the Ca2+ dependency of CTL cytotoxicity. Furthermore, we observed that CD8+ T cells from elderly mice differ clearly in their killing kinetics in comparison to adult mice. The elderly CD8+ T cells revealed significantly higher target lysis after 60 and 120 min against P815 and EL4 tumor cells and may mirror different killing pathways used by CD8+ T cells. The reasons for this different killing behavior are currently part of our further investigations.

Publications

• STIM2 drives Ca2+ oscillations through store-operated Ca2+ entry caused by mild store depletion. J Physiol. 2013 Mar 15;591(Pt 6):1433-45
  Thiel M, Lis A, Penner R
  
• TRPM7 is regulated by halides through its kinase domain. Cell Mol Life Sci, 2013 Mar 8
  Yu H, Zhang Z, Lis A, Penner R, Fleig A
  
• Measuring endogenous ICRAC and ORAI currents with the patch-clamp technique. Cold Spring Harb Protoc. 2014 Jun 2;2014(6):630-7
  AlAnsary D, Kilch T, Holzmann C, Peinelt C, Hoth M, Lis A
  
• Patch-clamp measurement of ICRAC and ORAI channel activity. Cold Spring Harb Protoc. 2014 Jun 2;2014(6):602-7
  AlAnsary D, Kilch T, Holzmann C, Peinelt C, Hoth M, Lis A
  
• The minimal requirements to use calcium imaging to analyze ICRAC Cold Spring Harb Protoc. 2014 Jun 2;2014(6):638-42
  AlAnsary D, Kilch T, Holzmann C, Peinelt C, Hoth M, Lis A
  
• A calcium-redox feedback loop controls human monocyte immune responses: The role of ORAI Ca2+ channels. Sci Signal. 2016 Mar 8;9(418):ra26
  Saul S, Gibhardt CS, Schmidt B, Lis A, Pasieka B, Conrad D, Jung P, Gaupp R, Wonnenberg B, Diler E, Stanisz H, Vogt T, Schwarz EC, Bischoff M, Herrmann M, Tschernig T, Kappl R, Rieger H, Niemeyer BA, Bogeski I