Abstract The steadily increasing elderly population and its rising incidence of organ failure have led to a burgeoning number of aged patients on the waitlist for solid organ transplants. Lymph nodes (LNs) play a critical role in controlling alloimmune responses and formation of immune tolerance to transplantation under costimulatory blockade. LN stromal cells are referred to as fibroblastic reticular cells (FRCs). FRC are the chief architect of LN by producing and maintaining the extracellular matrix (ECM) fibers upon which T cells that have entered through high endothelial cells crawl to encounter dendritic cells (DCs), which present allo-antigens. In addition to providing the LN scaffold, they also produce various chemokines that regulate the homing of T and B cells. The trafficking of T cells to the LN and proper positioning of DCs are critical requirements for the generation of iTregs following anti-CD40L treatment and suppression of alloreactive T cells. The role of aged FRCs in changing the stromal microenvironment in aging LNs is a novel concept central to the pathogenesis of alloimmunity in elderly transplant recipients, which remains to be fully explored. Pursuing our preliminary data, our main hypothesis is that aging-associated senescence of FRCs transforms them to pro-inflammatory myofibroblasts that create an immunostimulatory LN microenvironment that produces resistance against the promotion of graft acceptance under costimulatory blockade. Aged LNs contain a significant accumulation of ECM, and aged FRCs experience a high level of senescence, resulting in an increase in the population of pro-inflammatory T cells. FRCs are derived from lymphoid tissue organizer cells in a lymphotoxin β-receptor (LTβR)-dependent manner. We further hypothesize that LTβR signaling in aged FRCs plays a critical role in regulating their immunoregulatory function and the fate of transplant tolerance. Pursuant to our preliminary data, we will test the hypothesis that FRC therapy and/or targeted delivery of an LTβR agonist will rejuvenate the LN stroma of aged mice, supporting the tolerogenic effect of ant-CD40L. We are proposing three AIMS as follows. AIM 1 will study the mechanisms by which aging-associated senescence in FRCs regulates alloimmunity in the LN. AIM 2 will examine the importance of lymphotoxin pathways in aged LN stroma and transplant immunity. AIM 3 will study novel approaches to rejuvenate aged LN stroma to restore immune tolerance following anti-CD40L treatment.