An adaptive immune response is generated when naive T cells contact activated antigen-presenting cells in the secondary lymphoid organs. These tissues have a specialized architecture that facilitates efficient interaction between circulating lymphocytes and their target antigens. The formation and organization of the peripheral lymphoid organs are controlled by proteins of the TNF family and their receptors (TNFRs). Lymphoid tissue inducer (LTi) cells expressing lymphotoxin-β (LT-β) interact with stromal cells expressing the LT-β receptor in the developing embryo to induce chemokine production, which in turn initiates formation of the lymph nodes and Peyer’s patches. Similar interactions between lymphotoxin-expressing B cells and TNFR-Iexpressing follicular dendritic cells (FDCs) establish the normal architecture of the spleen and lymph nodes. B and T cells are partitioned into distinct areas within lymphoid tissue by specific chemokines.
To ensure that rare antigen-specific T cells survey the body effectively for pathogen-bearing antigen-presenting cells, T cells continuously recirculate through the lymphoid organs and thus can sample antigens brought in by antigen-presenting cells from many different tissue sites. The migration of naive T cells into lymphoid organs is guided by the chemokine receptor CCR7, which binds CCL21 that is produced by stromal cells in the T-cell zones of secondary lymphoid tissues and is displayed on the specialized endothelium of HEVs. L-selectin expressed by naive T cells initiates their rolling along the specialized surfaces of high endothelial venules, where contact with CCL21 induces a switch in the integrin LFA-1 expressed by T cells to a configuration with affinity for the ICAM-1 expressed on the venule endothelium. This initiates strong adhesion, diapedesis, and migration of the T cells into the T-cell zone. There, naive T cells meet antigen-bearing dendritic cells, of which there are two main populations: conventional dendritic cells, and plasmacytoid dendritic cells. Conventional dendritic cells continuously survey secondary tissues for invading pathogens and are the dendritic cells responsible for activating naive T cells. Contact with pathogens delivers signals to dendritic cells via TLRs and other receptors that accelerate antigen processing and the production of for-eign-peptide:self MHC complexes. TLR signaling also induces expression of CCR7 by dendritic cells, which directs their migration to T-cell zones of secondary lymphoid organs, where they encounter and activate naive T cells.
Macrophages and B cells can also process particulate or soluble antigens from pathogens to be presented as peptide:MHC complexes to T cells. However, whereas antigen presentation to naive T cells is uniquely mediated by dendritic cells, antigen presentation by macrophages and B cells enables the latter two cell types to recruit the effector activities of previously activated antigen-specific T cells. For example, as discussed in Chapter 11, by presenting antigens of ingested pathogens, macrophages recruit help from IFN-γ-producing CD4 T cells to augment their intracellular killing of these pathogens. Presentation of antigens by B cells recruits help from T cells to stimulate antibody production and class switching, a topic discussed further in Chapter 10. In all three types of antigen-presenting cells, the expression of co-stimulatory molecules is activated in response to signals from receptors that also function in innate immunity to signal the presence of infectious agents.
Priming of naive T cells by pathogen-activated dendritic cells.