The Role of CD40 in Naïve and Memory CD8+ T Cell Responses: a Dissertation

Abstract

Stimulation of CD40 on APCs through CD40L expressed on helper CD4 + T cells activates and “licenses” the APCs to prime CD8 + T cell responses. While other stimuli, such as TLR agonists, can also activate APCs, it is unclear to what extent they can replace the signals provided by CD40-CD40L interactions. In this study, we used an adoptive transfer system to re-examine the role of CD40 in the priming of naive CD8 + T cells. We find an approximately 50% reduction in expansion and cytokine production of TCR-transgenic T cells in the absence of CD40 on all APCs, and on dendritic cells in particular. Moreover, CD40-deficient and CD40L-deficient mice fail to develop endogenous CTL responses after immunization and are not protected from a tumor challenge. Surprisingly, the role for CD40 and CD40L are observed even in the absence of CD4 + T cells; in this situation, the CD8 + T cell itself provides CD40L. Furthermore, we show that although TLR stimulation improves T cell responses, it cannot fully substitute for CD40. We also investigated whether CD40-CD40L interactions are involved in the generation, maintenance, and function of memory CD8 + T cells. Using a virus infection system as well as a dendritic cell immunization system, we show that the presence of CD40 on DCs and other host APCs influences the survival of activated effector cells and directly affects the number of memory CD8 + T cells that are formed. In addition, memory CD8 + T cell persistence is slightly impaired in the absence of CD40. However, CD40 is not required for reactivation of memory CD8 + T cells. It seems that CD40 signals during priming also contribute to memory CD8 + T cell programming but this function can be independent of CD4 + T cells, similar to what we showed for primary responses. Altogether, these results reveal a direct and unique role for CD40L on CD8 + T cells interacting with CD40 on APCs that affects the magnitude and quality of primary as well as memory CD8 + T cell responses.