Lymphocyte homeostastis & regulation during aging

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

The size, composition, and dynamics of B cell subsets change with age, indicating shifts B cell[unreadable] homeostasis and selection. BLyS and its receptors play a central role in B cell homeostasis.[unreadable] Consequently, we hypothesize that BLyS mediated homeostatic processes are perturbed in aged[unreadable] individuals, leading to alterations in the dynamic and selective events that shape and maintain peripheral[unreadable] B cell pools. These studies will probe the relationship between BLyS-mediated homeostatic processes[unreadable] and age-associated changes among B cells. In aim 1, we will determine whether age-associated[unreadable] shifts in B cell subsets and repertoire selection rely on BLyS-BR3 mediated processes. Marrow[unreadable] and splenic.B lineage subsets of A/WySnJ and A/J mice at various ages will be characterized for[unreadable] representation, magnitude and turnover rate. In addition, repertoire diversity of immature, transitional,[unreadable] follicular, and MZ subsets will be assessed in A/J and A/WySnJ mice at various ages. These studies will[unreadable] employ limiting dilution and fine specificity analyses of the influenza hemagglutinin (HA)-specific response,[unreadable] as well as CDR3 length analyses. In aim 2, we will determine whether the lengthened lifespan of[unreadable] mature B cells in aged mice reflects enhanced ability to capture BLyS-BR3 signals. The levels of[unreadable] BLyS binding and BLyS receptor expression, as well as downstream mediators of BLyS and APRIL[unreadable] signaling, be followed as individuals age. We will establish whether these shifts reflect selection versus an[unreadable] intrinsic property of developing B cells in aged mice through analysis of reciprocal bone marrow chimeras.[unreadable] We will determine whether aged B cells enjoy a competitive advantage over young B cells in adoptive[unreadable] transfer, and whether this is abrogated by exogenous SLyS administration. In aim 3, we will determine[unreadable] whether the age-associated appearance of serum autoantibodies relies on BLyS mediated events.[unreadable] The experiments in this aim will also use the A/WsnJ and A/J strains for comparison. Age-associated[unreadable] appearance of ANAs will be followed, the B lineage subsets responsible for ANA antibody formation will[unreadable] be identified, and the repertoires of ANA producing clonotypes assessed. In addition, we will directly test[unreadable] whether transitional selection against autoreactive specificities changes with age through cloning and[unreadable] analysis of expressed VLVH pairs. In aims 1 -3, we will determine whether shifts in kinetics, selection[unreadable] and/or BLyS receptor expression in aged B cell populations reflect downstream outcomes of reduced EBP[unreadable] output, with Dr. Allman. In aim 4, we will determine whether manipulation of BLyS levels can restore[unreadable] robust B and T cell responses following immunization. We will examine the immune response to[unreadable] influenza HA in aged and young individuals to determine whether pretreatment with BLyS or BLyS[unreadable] receptor agonists restore litres of HA-specific antibody, as well as elevated HA-specific T cell, and B cell[unreadable] frequencies following immunization.