Levels of CD40 expression on dendritic cells dictate tumour growth or regression.
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.
Murugaiyan
G
G
National Centre for Cell Science, Ganeshkhind, Pune, India.
Martin
S
S
Saha
B
B
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism*; D002455:Cell Division / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
D019013:CD40 Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016753:Interleukin-10; D007371:Interferon-gamma