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