Ganglioside-exposed dendritic cells inhibit T-cell effector function by promoting regulatory cell activity.
Tumour pathogenesis is characterized by an immunosuppressive microenvironment that limits the development of effective tumour-specific immune responses. This is in part the result of tumour-dependent recruitment and activation of regulatory cells, such as myeloid-derived suppressor cells and regulatory T cells in the tumour microenvironment and draining lymph nodes. Shedding of gangliosides by tumour cells has immunomodulatory properties, suggesting that gangliosides may be a critical factor in initiating an immunosuppressive microenvironment. To better define the immunomodulatory properties of gangliosides on antigen-specific T-cell activation and development we have developed an in vitro system using ganglioside-treated murine bone-marrow-derived dendritic cells to prime and activate antigen-specific CD4(+) T cells from AND T-cell receptor transgenic mice. Using this system, ganglioside treatment promotes the development of a dendritic cell population characterized by decreased CD86 (B7-2) expression, and decreased interleukin-12 and interleukin-6 production. When these cells are used as antigen-presenting cells, CD4 T cells are primed to proliferate normally, but have a defect in T helper (Th) effector cell development. This defect in Th effector cell responses is associated with the development of regulatory T-cell activity that can suppress the activation of previously primed Th effector cells in a contact-dependent manner. In total, these data suggest that ganglioside-exposed dendritic cells promote regulatory T-cell activity that may have long-lasting effects on the development of tumour-specific immune responses.
Jales
Alessandra
A
Department of Microbiology, Immunology, and Tropical Medicine, George Washington University School of Medicine, Washington DC, USA.
Falahati
Rustom
R
Mari
Elisabeth
E
Stemmy
Erik J
EJ
Shen
Weiping
W
Southammakosane
Cathy
C
Herzog
Dallen
D
Ladisch
Stephan
S
Leitenberg
David
D
D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D005732:Gangliosides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
D005732:Gangliosides; D011948:Receptors, Antigen, T-Cell