T helper cell mediated immunity against retrovirus-induced lymphoma
01 / 2001 - 12 / 2004
- Aim: The purpose of this proposal is to elucidate the mechanism of T cell help for optimal recruitment of the different effector components of the immune system in the control of retrovirus-induced lymphoma.T helper cells play a central role in immunity against retrovirus-induced lymphoma. We have established the importance of tumor-specific T helper epitopes, rather than non-tumor related T helper epitopes, in a synthetic peptide based vaccine. The specific nature of the required T cell help presumably involves the interaction with specialized antigen-presenting cells in addition to the local production of cytokines. Vaccination with a retrovirus-encoded T helper peptide in C57BL/6 mice results in strong protection even against MHC class II negative tumors. This indicates the requirement of cross-presentation of tumor antigens by local APC and the importance of the T helper-APC interaction. Tumor eradication was mediated primarily by retrovirus-specific cytotoxic T lymphocytes. The contribution of CD4+ effector function and antibodies has remained underexposed. The advantage of this model system is the availability of the T cell epitopes of both the CD4 T helper arm and the CD8 effector arm of the immune system. Herewith we can study the relationship between both of these cell types and specialized APC to obtain optimal protective immunity. - Plan of investigation: 1. Investigation of the contribution of different T helper epitopes. Thus far three different T helper peptides has been identified. These will be investigated for their efficacy in inducing protective immunity. The quantity and quality (type) of the T helper responses and the CD8 responses will be analyzed in detail. 2. T helper responses will be studied in different genetic backgrounds. C57BL/6 mice are predisposed to generate type 1 immune responses. We will study other mouse strains and F1 mice that are more prone to develop type 2 responses. The quality of CD4 and CD8 T cell responses and tumor protection will be monitored. 3. TCR transgenic mice will generated carrying the T cell receptor chains of the tumor-protective T helper clone. Herewith we will be able to follow and manipulate tumor-specific CD4 T cells in vitro and in vivo. The transgenic T cells will be used in vitro to polarize them to TH1and TH2 type cells. These cell types will be used to study their interaction with DC and study the effects on CTL induction capacity and tumor protection. 4. The interaction between T helper cells and dendritic cells will be studied. The role of several receptor-ligand interactions will be investigated. The involvement of TNF-receptor family members such as CD40, OX40, 4-1BB, CD27 and CD30 can be expected. Blocking and stimulatory reagents against these molecules and most of their ligands are available as well as several transgenic and knock-out mice. The effects on the CD4 and CD8 response and tumor protection will be investigated in detail. 5. The contribution of the B cell response will be investigated. The role of retrovirus-specific antibodies will be studied as a mode of antigen-delivery to APC and as a potential role in effector mechanisms. The availability of different FcgR deficient mice will enable us to explore the relevance of the different Ig isotypes and the relationship of antibody to TH type responses in the control of these tumors. - Possible results and relevance: These studies are expected to provide insight into the cellular and molecular events within the immune system involved in the control of highly aggressive tumorigenic cells. This will enable us to design novel strategies to specifically manipulate and selectively activate the most potent regulatory and effector cells.