The sequence of events in the responses of CD4+ T cells involves the initial activation of these cells in lymphoid organs to generate effector and memory cells, migration of many of these effector cells to sites of infection, and elimination of infectious pathogens at these sites (Fig. 1). We described the early steps in the activation of T cells in Chapter 9, and we will describe the generation and functions of effector CD4+ T cells in this chapter.
Fig1. Steps in CD4+ T cell–mediated immune responses. CD4+ T cells recognize peptides that are derived from protein antigens and presented by dendritic cells in secondary lymphoid organs. The T lymphocytes are stimulated to proliferate and differentiate into effector (and memory) cells, which enter the circulation and migrate to sites of infection in peripheral tissues. In the tissues, effector T cells recognize the antigen and respond by secreting cytokines that recruit more leukocytes and activate phagocytes to eradicate the infection.
Effector CD4+ T cells differentiate from naive T cells in secondary lymphoid organs, and most of the effector cells leave these organs and migrate to peripheral sites of infection, where they function to eliminate microbes. This migration of effector T cells to sites of infection is dependent on endothelial adhesion molecules and chemokines expressed at these sites. Although migration is largely independent of antigens, T cells that recognize antigen in tissues may be preferentially retained there. Once in the tissues, the T cells encounter microbial anti gens presented by macrophages and other antigen-presenting cells (APCs). T cells that specifically recognize antigens receive signals through their antigen receptors that increase the affinity of integrins for their ligands. Two of these integrins, VLA-4 and -5 (very late antigens-4 and -5, also known as integrins α4β1 and α5β1, respectively), bind to fibronectin in extracellular matrices, and a third adhesion molecule, CD44, which is also highly expressed on activated T cells, binds to hyaluronan. In addition, chemokine receptors expressed on activated T cells bind chemokines that are produced in tissues. As a result of these adhesive and chemotactic interactions, antigen-specific effector T cells that encounter the antigen at the extravascular site stay in the tissue long enough to perform their functions. T cells not specific for the antigen that migrate into a site of inflammation may die in the tis sue or return to the circulation through lymphatic vessels. Some memory T cells also migrate to peripheral tissues, using the same adhesion molecules and chemokine receptors as do effector cells.
A fraction of the CD4+ T cells that are activated in secondary lymphoid organs do not exit the organs but migrate into lymphoid follicles within the organs, where they help B cells to produce high-affinity antibodies of different classes. These helper T cells are called T follicular helper (Tfh) cells; their development, properties, and functions in humoral immune responses are described in Chapter 12.
In cell-mediated immune responses against phagocytosed microbes, T cells specifically recognize microbial antigens, but recruited phagocytes and other myeloid cells destroy the pathogens. Thus, effector T cells of the CD4+ lineage link specific recognition of microbes with the activation of other leukocytes that destroy the microbes. This fundamental concept was first appreciated from studies of cell-mediated immunity to the intracellular bacterium Listeria monocytogenes (Fig. 10.3). It was shown that mice infected with a low (sublethal) dose of Listeria were protected from challenge with higher doses that were lethal in previously uninfected animals. Protection could be transferred to naive animals with lymphocytes (later shown to be T lymphocytes) from the infected mice but not with serum, the fluid fraction of clotted blood that contains antibodies. These results demonstrated that specific protection against an intracellular bacterial infection was mediated by T cells. However, in vitro, the bacteria were killed not by T cells from immune animals but by activated macrophages, emphasizing the central role of macrophages in microbe elimination. Such studies established that defense against intracellular microbes required cooperative interactions between antigen-specific T cells and microbicidal phagocytes, and we now know this type of interaction is an important component of cell-mediated immunity.
Fig2. Cell-mediated immunity to Listeria monocytogenes. Immunity to L. monocytogenes is measured by inhibition of bacterial growth in the spleens of animals inoculated with a known dose of viable bacteria. Such immunity can be transferred to normal mice by T lymphocytes (A) but not by serum (B) from syngeneic mice previously immunized with killed or low doses of L. monocytogenes. In an in vitro assay of cell-mediated immunity, the bacteria are killed by activated macro phages and not by T cells (C).
Ingestion and elimination of microbes by phagocytes is also a major reaction of innate immunity, and T cells greatly enhance this function of phagocytes. As we discussed in Chapter 4, phagocytes recognize microbes and are activated by pathogen associated molecular patterns, such as Toll-like receptor (TLR) ligands, and they are capable of destroying a variety of microbes. However, some infectious pathogens have evolved to resist this mechanism of innate immunity and can survive and even replicate inside macrophages. In such infections, T cells recognize microbial protein antigens and activate the phagocytes, enabling them to destroy microbes that may not be eliminated by the innate functions of the macrophages in the absence of T-cell help. CD4+ effector T cells activate phagocytes via surface molecules, principally CD40 ligand (CD40L, CD154) and secreted cytokines. We will see how these signals cooperate when we discuss the activation of macrophages later in this chapter.
Inflammation, consisting of leukocyte recruitment and activation, accompanies many of the reactions of CD4+ T lymphocytes. This T cell–dependent inflammation serves as an antimicrobial defense mechanism but also can be injurious to tissues. When a T-cell reaction causes injury, it is called delayed-type hypersensitivity (DTH), the term hypersensitivity referring to an excessive or damaging immune response. DTH frequently occurs together with protective cell-mediated immunity against microbes and may be the cause of much of the pathology associated with certain types of infectious and auto immune diseases.
Because the functions of CD4+ T cells are mediated in large part by cytokines, there has been great interest in defining these cytokines, which cells produce them, and how they function. An important discovery was the identification of populations of CD4+ effector T cells that produce different cytokines and, therefore, perform distinct functions. We will begin with a description of the major properties of these sub sets and then describe the development and functions of each population.
