The role of 4-1BB costimulation in the regulation of T cell responses

Optimal T cell activation and proliferation requires at least two signals from cell surface molecules. T cells first encounter antigen in the form of short peptides bound to major histocompatibility complex (MHC) molecules. The interaction of the T cell receptor (TCR) with the MHC peptide complex sends the first signal and provides the specificity for the T cell response. The second signal is delivered by costimulatory pathways like CD28 and CD40 and is critical for the proper development of T cell responses.;This thesis examines the role of 4-1BB-4-1BBL interaction in T cell responses. 4-1BB, a molecule that is structurally related to the large family of TNF receptor molecules, is expressed on the surface of activated T cells, and 4-1BB ligand (4-1BBL) is expressed on antigen presenting cells (APC). In an allogeneic model of T cell activation, 4-1BB was expressed late after activation and signals delivered through 4-1BB promoted CD8 T cell proliferation and cytokine secretion. In a second model, mice that are deficient for 4-1BBL were infected with lymphocytic choriomeningitis virus (LCMV) to examine T cell responses in-vivo. Anti-viral CD8 T cell expansion was reduced 2--3 fold in 4-1BBL-deficient mice and CD8 T cell memory was also deficient. In contrast to the CD8 T cell response, CD4 T cell expansion was unaffected in response to alloantigens and LCMV, but the establishment of CD4 T cell memory was defective in 4-1BBL-deficient mice. Though T cell memory was diminished in the absence of 4-1BB costimulation, 4-1BB was not required for maintenance and turnover of memory T cells. In support of its role as an important mediator of T cell responses, 4-1BBL-deficient mice showed weaker CD8 T cell responses to peptide vaccination that impaired their ability to mount secondary immune responses to viral challenge. Altogether, 4-1BB serves as a T cell costimulatory molecule that enhances primary CD8 T cell responses and long-term T cell memory.