The lung is a major site of exposure to the outside world in air-breathing species. Lung immunity has developed to recognize pathogens and activate appropriate responses, to temper inflammation in response to nonpathogenic exposures, and to turn off immune responses when danger signals have been shut down. T lymphocytes play a major role in lung immunity predominantly as CD4+ and CD8+ T cells involved in adaptive immunity. A number of smaller subsets of T lymphocytes also play critical roles in early immune responses to pathogens and to stimulate adaptive immune responses. Long-lived memory CD4+ and CD8+ T cells are crucial for host protection from pathogens, but they also may drive chronic disease states such as asthma. This chapter reviews the basic biology of T lymphocytes and their relevance in the lung in health and disease.
Lymphocytes make up approximately 10% of leukocytes in the blood and nearly 70% of leukocytes in the normal human lung.1 In both sites, a majority of lymphocytes are T lymphocytes. Lymphocytes include T and B cells and are small, mononuclear cells with a characteristic large nucleus-to-cytoplasm ratio in the resting state. T lymphocytes have their origin in the thymus. T lymphocytes are essential for adaptive immune responses, the type of immunity that develops over a period of days to weeks and fine-tunes an immune response to limit a specific pathogen or insult. The majority of T lymphocytes express alpha-beta (α/β) T cell antigen receptors (TCRs) on the cell surface. The α/β TCR consists of two polypeptide chains with a variable region that binds to antigen, a constant region, and an anchor to the cell membrane. During development in the thymus, T cells undergo TCR gene rearrangement to generate a receptor that has an antigen-binding structure. Each mature T cell bears only this TCR with its unique specificity for antigen binding. Approximately 106 different TCRs develop and allows an individual to respond to an extraordinary range of antigens throughout life. After exposure to a new antigen, TCRs expressed on conventional CD4- and CD8-expressing T lymphocytes develop even finer antigen-binding capabilities through a process called affinity maturation.
There are also unconventional subsets of T lymphocytes that express T cell receptors with restricted diversity and include NKT and MAIT cells that express an α/β TCR, and gamma-delta (γ/δ) TCR-expressing cells. These populations of T lymphocytes are typically fewer in number and more prominent at sites of pathogen exposure, such as the mucosal surfaces. They express preformed receptors that bind to common pathogen components. This preset ability to bind and react to pathogens allows them to respond quickly, leading to early release of cytokines. NKT, MAIT, and γ/δ T cells are part of the early immune response to pathogens and other insults and provide signals to initiate and direct CD4 and CD8 T cell activation in the adaptive immune response.