Core C: Thymic and peripheral Aspects of T cell Aging and Rejuvenation

Sempowski, Gregory

Abstract

Using innovative forward-thinking mouse models and approaches, the Projects in this comprehensive discovery-based Thymus Rejuvenation PPG seek to (i) identify mechanisms behind reduced thymic production and impaired peripheral maintenance of T cells with aging and stress, and (ii) develop combined strategies to ameliorate these defects and improve immune defense against infection and cancer in the elderly. Critical to the translation potential of project-identified mechanisms, pathways and therapeutic targets in future programs, is proof-of-concept verification of applicability of mouse targets/pathways to human thymus aging, and centralized assessment of thymic function (i. e. sjTREC). To meet this need a central Human Target Verification and Thymic Function Core (Core C) has been integrated into this Program Project. At the center of the Core is the Duke Human Vaccine Institute (DHVI) Human Thymus Tissue Biobank, which contains more than 900 healthy-donor human thymus tissues (ages 1 day to 80 years). The Thymus Biobank consists of FFPE tissue blocks, snap-frozen frozen tissue chunks, and DMSO-cryopreserved thymocytes and T cell depleted stroma. The Biobank has been maintained by the Core leader, Dr. Greg Sempowski, for 15+ years and has been extensively characterized by Dr. Sempowski and Core co-investigator/pathologist, Dr. Laura Hale. Dr. Hale's immunohistochemical analysis and Dr. Sempowski's molecular analysis (i. e. gene expression and TCR rearrangement) of tissues from the Biobank laid the foundation for our modern understanding of changes in human thymus architecture and function across the lifespan. Core C will accelerate proof-of-concept verification of project-identified mouse therapeutic targets/pathways in human thymus aging/rejuvenation and independently monitor thymic output with three focused specific aims: (SA1) Define and characterize age, sex and phenotypically applicable human thymus tissues panels to meet project- specific translation verification needs. Provide central histologic and molecular analyses on tissue panels; (SA2) provide centralized expert board-certified pathology support for human and mouse tissue staining, scoring and analysis; and (SA3) provide standardized, quality-controlled assay support for mouse sjTREC assays. Successful delivery of Core C services to Projects 1-4 and Core D will: (i) add considerable value to this overall program, (ii) be a key component of overall program synergy, and most importantly, (iii) provide critical proof-of-concept verification of applicability of mouse targets/pathways to human thymus aging/rejuvenation to ameliorate age-associated immune deficiencies and improve immune defense against infection and cancer in the elderly.

Public Health Relevance

The overall goal of the Human Target Verification and Thymic Function Core (Core C) is to facilitate verification of applicability of Program-identified mouse therapeutic targets/pathways to human thymus aging/rejuvenation and provided centralized assessment of thymic function. This will be accomplished by providing applicable human thymus tissues panels to meet project-specific translation verification needs and by performing central histologic and molecular analyses on tissue panels and project-generated specimens. Successful delivery of Core C services to Projects 1-4 and Core D will provide critical proof-of-concept verification of applicability of mouse targets/pathways to human thymus aging to ameliorate age-associated immune deficiencies and improve immune defense against infection and cancer in the elderly.