Levels of CD40 expression on dendritic cells dictate tumour growth or regression

Abstract

Tumour regression requires activation of T cells. It has been shown that the interaction between T cell-expressed CD40-ligand (CD40-L) and antigen-presenting cell-expressed CD40 plays a crucial role in T cell activation. CD40-L- or CD40-deficient mice are susceptible to tumour growth. CD40-based therapies are also shown to control tumour growth significantly, suggesting that CD40-CD40-L interaction induces anti-tumour T cell responses and tumour regression. We demonstrate that the anti-tumour T cell response can be modulated reciprocally as a function of the levels of CD40 expression. At low expression levels, CD40 promotes tumour growth; at higher expression levels, CD40 induces tumour-regressing T cell response. Dendritic cells (DC) sorted onto major histocompatibility complex (MHC)-II expression are found to be similar in CD40 and CD80 expression. The MHC-II^hi/CD40^hi DC induce interleukin (IL)-12-dominated and T helper 1 (Th1)-type response, whereas MHC-II^lo/CD40^lo DC promote high IL-10 and Th2-type T cells. The T cells induced by these DC also differ in terms of regulatory T cell markers, lymphocyte activation gene-3 (LAG-3) and glucocorticoid-induced tumour necrosis factor (TNF) receptor family-related gene (GITR). Thus, we report for the first time that CD40-induced effector T cell response depends on CD40 expression levels in vivo.