Naïve T lymphocytes are activated by antigen and costimulators in peripheral lymphoid organs, and proliferate and differentiate into effector cells that migrate to any site where the antigen (microbe) is present (see
Fig. 5.9 ). One of the earliest responses of CD4+ helper T cells is secretion of the cytokine IL-2 and expression of high-affinity receptors for IL-2. IL-2 is a growth factor that acts on these T lymphocytes and stimulates their proliferation, leading to an increase in the number of antigen-specific lymphocytes.
The functions of helper T cells are mediated by the combined actions of CD40-ligand (CD40L) and cytokines. CD40 is a member of the TNF-receptor family, and CD40L is a membrane protein homologous to TNF. When CD4+ helper T cells recognize antigens being displayed by macrophages or B lymphocytes, the T cells express CD40L, which engages CD40 on the macrophages or B cells and activates these cells.
Some of the activated CD4+ T cells differentiate into effector cells that secrete different sets of cytokines and perform different functions (
Fig. 5.10 ). Cells of the TH1 subset secrete the cytokine IFN-γ, which is a potent macrophage activator. The combination of CD40-and IFN-γ– mediated activation results in “classical” macrophage activation (Chapter 3), leading to the induction of microbicidal substances in macrophages and the destruction of ingested microbes. TH2 cells produce IL-4, which stimulates B cells to differentiate into IgE-secreting plasma cells; IL-5, which activates eosinophils; and IL-13, which activates mucosal epithelial cells to secrete mucus, and induces the “alternative” pathway of macrophage activation, which is associated with tissue repair and fibrosis (Chapter 3). Eosinophils bind to and kill IgE-coated pathogens such as helminthic parasites. TH17 cells, so called because the signature cytokine of these cells is IL-17, recruit neutrophils and monocytes, which destroy some extracellular bacteria and fungi and are involved in certain inflammatory diseases.
Activated CD8+ T lymphocytes differentiate into CTLs that kill cells harboring cytoplasmic microbes, thereby eliminating otherwise hidden reservoirs of infection. The principal mechanism of killing by CTLs depends on the perforin–granzyme system. Perforin and granzymes are stored in the granules of CTLs and are rapidly released when CTLs engage their targets (cells bearing the appropriate class I MHC–bound peptides). Perforin binds to the plasma membrane of the target cells and promotes the entry of granzymes, proteases that specifically cleave and thereby activate cellular caspases (Chapter 2), which induce the apoptosis of target cells.
The responses of T cells are regulated by a balance between costimulatory and inhibitory receptors. The major costimulatory receptor is CD28, mentioned earlier as the molecule that recognizes B7 ligands on APCs and provides second signals that work together with antigen recognition. Other proteins of the CD28 family include two “coinhibitory” receptors, CTLA-4 and PD-1, which block signals from the TCR and from CD28 and thus terminate T cell responses. Blocking these coinhibitors has proved to be a powerful approach for enhancing anti-tumor immune responses (Chapter 6).
Humoral Immunity: Activation of B Lymphocytes and Elimination of Extracellular Microbes
Upon activation, B lymphocytes proliferate and then differentiate into plasma cells that secrete different classes of antibodies with distinct functions (
Fig. 5.11 ). There are two major pathways of B-cell activation.