The dynamic interactions among CD4(+) T helper, antigen- presenting cells and CD8(+) cytotoxic T cells

The immune system comprises many different types of immune cells which function cooperatively to achieve its full capacity to fight against infection (immune activation) and at the same time retain self unharmed (immune tolerance). Imbalance between these two immune actions results in diseases such as tumor development and autoimmune diseases. Antigen-presenting cells, especially dendritic cells, are the most important cells that initiate immune responses by processing and presenting antigen, self and non-self, to naïve CD4 + and CD8+ T cells. Therefore, it is critical to understand the interactions among these cells at the cellular and molecular level in order to modulate the system, turning up or turning down, to ultimately control diseases. The work presented in this dissertation has revealed a complex and dynamic interactions among these cells. Specifically, we have found: (1) CD4 + T cells can provide potent help for DCs to cross- or direct-prime CD8+ cytotoxic T cells especially when antigen level is low. If antigen dose is high enough, DCs can prime CD8+ CTL in a CD4+ T helper-independent manner (see Chapter 2). (2) CD4 + T help comprises CD40-dependent and CD40-independent pathways. The latter is further dissected into two components: CD4+ T cell-DC sensitization and CD4+-CD8+ T cells communication via lymphokines (see chapter 3). (3) CD4+ T cell activation prior to tolerance induction elicits effector functions by providing help for expansion of CD8+ T cells, generating synergistic anti-tumor effect with CD8+ T cells. (See chapter 4). (4) Initial proliferation of CD4+ and CD8+ T cells is totally CD40-independent but the expanded T cells in the absence of CD40 are short-lived; The role of CD40 is to sustain expanded T cells in order to generate long-term effector functions. The lack of CD40L-CD40 interaction is, therefore, favors tolerance induction (see chapter 5) Together, these findings further elucidate the multi-step nature of immune regulations and provide important information for immune intervention to fight against cancer and other immunological diseases.