ABSTRACT
Accumulating evidence suggests that CD4 help is needed at the memory stage to mount effective secondary CD8 T cell responses. In this paper, we report that memory CD4 T cells can provide efficient help to memory CD8 T cells after interaction of the two lymphocytes with distinct dendritic cells. Provision of help to CD8 T cells required direct cell-cell contact and involved both IL-2 and CD40 ligation, within a CD4-CD8 T cell synapse. Thus, following antigenic interaction with APCs, activated memory CD4 and CD8 T cells appear to separate from their respective APCs before meeting each other for help provision, regardless of their Ag specificity. CD4 help for memory CD8 T cells therefore appears to be conditioned primarily not by Ag specificity but by activation status.
Subject(s)
Antigen Presentation/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , CD40 Antigens/immunology , CD40 Antigens/metabolism , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/metabolism , Carcinoma, Lewis Lung/immunology , Carcinoma, Lewis Lung/pathology , Cell Communication/immunology , Cell Line, Tumor , Cell Proliferation , Coculture Techniques , Cytotoxicity, Immunologic/immunology , Dendritic Cells/cytology , Female , Flow Cytometry , Granzymes/metabolism , Immunologic Memory/immunology , Interleukin-2/immunology , Interleukin-2/metabolism , Lymphocyte Activation/immunology , Major Histocompatibility Complex/genetics , Major Histocompatibility Complex/immunology , Male , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
Help from CD4 T cells may be required for optimal generation and maintenance of memory CD8 T cells and also for optimal Ag reactivation. We examined whether the helper cell and the CD8 killer cell need to have the same Ag specificity for help to be effective during interactions of memory T cells with mature APC. This is important because virus and tumor Ag-specific CD4 T cell responses are selectively impaired in several chronic viral infections and malignancies. We performed studies in vitro and in vivo and found that functional memory CD4 T cells generated from a distinct antigenic source (heterospecific helpers) could provide direct and effective help to memory CD8 T cells. Functional heterospecific memory CD4 T cells could also rescue secondary CD8 T cell responses in an experimental tumor model in which homospecific CD4 help was impaired. This could provide a rationale for immunotherapy strategies designed to bypass impaired homospecific help.
