REGULATION OF CD4 EFFECTOR &MEMORY RESPONSES WITH AGING

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION: This proposal aims to define the basis for impaired responsiveness of CD4 T cells associated with age. These investigators demonstrate a defect in the aged naive TCR transgenic Th cell's ability to produce IL-2 in vitro. They demonstrate that the low IL-2 production in vitro leads to poor cell expansion and the incomplete generation of effector cells. This defect can be reversed with exogenous IL-2 addition and to some extent by inflammatory cytokines IL-1, IL-6 and TNF-a. However, when rescued effectors (exogenous IL-2 addition) are transferred in vivo they produce memory cells that are still reduced in their ability to produce IL-2 in vitro. These data lead to a central hypothesis suggesting that the development of Th cells is impaired in aged animals in some way that leads to a permanent impact on the ability of the CD4 cells to produce IL-2. This defect in IL-2 production is then responsible for the suppressed primary and memory immune responses seen in aged animals. Dr. Swain outlines three specific aims to extend their initial analysis of Th cell function in aged animals. Using an adoptive transfer protocol into unirradiated recipients, they will monitor the development of effector Th cells in vivo under different antigen doses, different adjuvants, and different priming environments. They will measure IL-2 production, changes in activation markers, rounds of division, cell loss and effector cell function across aged and young T cells transferred into aged or young recipients. In the second specific aim, they will generate effector cells in vitro (+/- IL-2 or inflammatory cytokines) and then adoptively transfer these cells into ATXBM non-transgenic syngeneic recipients to evaluate the generation of memory cells in vivo. They will measure a series of cellular characteristics associated with memory function; rapid proliferation, rapid cytokine production, increased antigen sensitivity, decreased co-stimulatory requirements, class II independent longevity, resistance to apoptosis and slow in vivo turnover. In the last specific aim, they explore the effects of 'cellular age' on T cell function by artificially aging young naive T cells in vivo after thymectomy and using these (aged for different times in vivo) as a source of cells for transfer studies.