Mechanisms of T cell activation: co-stimulation
In the normal host immune system, T-lymphocytes aid in both surveillance and clearance of neoplastic cells. In the context of malignancy, the host immune system generally responds to cancer cells in two ways, either by reacting against tumor-specific antigens (TSA), unique malignancy-associated molecules, or tumor-associated antigens (TAA), molecules that are expressed by cancer cells and normal cells but have divergent post-translational modifications.25,26 The antigen presenting cells (APCs), including dendritic cells, natural killer cells, macrophages, and antibody-producing B lymphocytes, sample and process tumor-specific or tumor-associated antigens and present them as TSAs or TAAs to MHC-I or MHC-II molecules on the surface of APCs. T-lymphocytes recognize those antigens (CD4 T-lymphocytes recognize MHC-II and CD8 T-lymphocytes recognize MHC-I, respectively) and attach to them via TCRs. To fully activate T-lymphocytes, however, a second signal is required, mediated by either cytokines or the engagement of co-stimulatory molecules such as B7.1 (CD80) or B7.2 (CD 86) on APCs. After the two signals co-stimulation, a single T-lymphocyte clone that recognizes a specific tumor antigen is clonally expanded. Compared to helper T-lymphocytes, cytotoxic T-lymphocytes are less reliant on CD28 for activation, but do require signals from other co-stimulatory molecules such as CD70 and CD137. Meanwhile, during the process of T-lymphocyte activation, cytokines (IL-12, IL-6, etc.) induce further differentiation of T-lymphocytes into mature helper T-lymphocytes, Th1 or Th2, each performing a specific task in furthering the immune response.27