Antigen is the necessary first signal for the activation of lymphocytes, ensuring that the resulting immune response is antigen specific. Because CD4+ and CD8+ T lymphocytes recognize pep tide-MHC complexes, they respond to protein antigens, the natural source of peptides, or to chemicals that bind to and modify proteins, thus creating novel antigenic determinants. Protein antigens that cross epithelial barriers or are produced in tissues are captured by DCs and transported to lymph nodes. Antigens that enter the circulation may be captured by DCs in the spleen. As discussed in Chapter 6, both naive T cells and mature DCs are drawn to the T-cell zones of secondary lymphoid organs by chemokines produced at these sites that engage the CCR7 chemokine receptor on the cells. By the time the mature DCs reach the T-cell areas, they display antigenic peptides on MHC molecules and also express costimulatory molecules. Some soluble protein antigens in the lymph may be delivered to lymph nodes independent of DCs and are taken up, processed, and presented as peptide-MHC complexes by resident DCs within the lymph nodes. DCs present peptides derived from endocytosed protein antigens mainly in association with MHC class II molecules to naive CD4+ T cells and peptides derived from cytosolic and nuclear proteins, as well as endocytosed proteins that gain access to the cytosol, are displayed by MHC class I molecules to naive CD8+ T cells.
Naive T lymphocytes move around within secondary lymphoid organs transiently interacting with many DCs and stop when they recognize the antigen for which they express specific receptors. T cells are in constant motion, mainly guided by a network of conduits produced by fibroblastic reticular cells (FRCs) in the T-cell zone of the lymphoid organs. The DCs that migrate to or are resident in lymphoid organs adhere to the FRC conduits, are relatively immobile, and simultaneously present many different antigens. T cells move along the conduits, making successive contacts with different DCs. T-cell recognition of antigens being displayed by these DCs results in the generation of biochemical signals that lead to rapid arrest of the T cells. This process stabilizes the contact between the anti gen-specific T cells and the relevant antigen-expressing APC and allows the activation program of these T cells to be initiated.
Differentiated effector T cells can respond to antigens presented by cells other than DCs. In humoral immune responses, B cells present antigens to helper T cells and are the recipients of activating signals from the helper cells; in cell-mediated immune responses, macrophages present antigens to, and respond to, CD4+ T cells; and any nucleated cell can present antigens to and be killed by CD8+ CTLs.
