Effector T cells that enter tissues but do not recognize their cognate antigen are not retained there. They either undergo apoptosis locally or enter the afferent lymphatics and migrate to the draining lymph nodes and eventually return to the bloodstream. Thus, T cells in the afferent lymph that drains tissues are memory or effector T cells, which characteristically express the CD45RO isoform of the cell-surface molecule CD45 and lack L-selectin (see Fig. 11.6). Effector T cells and some memory T cells have similar trafficking phenotypes, as we discuss later (see Section 11-22), and both seem to be committed to migration through, and in some cases, retention within, barrier tissues that are the primary sites of infection. In addition to allowing effector T cells to clear all sites of infection, this pattern of migration allows them to contribute, along with memory cells, to protecting the host against reinfection with the same pathogen.
11-5 TH1 cells coordinate and amplify the host response to intracellular pathogens through classical activation of macrophages.
Type 1 responses (see Fig. 11.5) are important for the eradication of those pathogens that have evolved mechanisms to survive and replicate within macrophages—for example, viruses, and bacterial and protozoan pathogens that can survive inside macrophage intracellular vesicles. In the case of viruses, a TH1 response is generally involved in helping to activate the CD8 cytotoxic T cells that will recognize virus-infected cells and destroy them (see Chapter 9). TFH cells that differentiate in type 1 responses induce the production of subclasses of IgG antibodies that neutralize virus particles in the blood and extracellular fluid. In the case of intracellular bacteria such as mycobacteria and Salmonella, and of protozoa such as Leishmania and Toxoplasma, which all take up residence inside macrophages, the role of TH1 cells is to activate macrophages to heighten their microbicidal function (Fig 11.10).
Pathogens of all types are ingested by macrophages from the extracellular fluid, and are often destroyed without the need for additional macrophage activation. In several clinically important infections, such as those caused by mycobacteria, ingested pathogens are not killed, and can even set up a chronic infection in macrophages and incapacitate them. Such microorganisms are able to maintain themselves in the hostile environment of phagosomes— shielded from the effects of both antibodies and cytotoxic T cells—by inhibiting the fusion of phagosomes and lysosomes, or by preventing the acidification required to activate lysosomal proteases. Nevertheless, peptides derived from such microorganisms can be displayed by MHC class II molecules on the macrophage surface, where they are recognized by antigen-specific effector TH1 cells. The TH1 cell is stimulated to synthesize membrane-associated proteins and soluble cytokines that enhance the macrophage’s antimicrobial defenses and enable it to either eliminate the pathogen or control its growth and spread. This boost to antimicrobial mechanisms is known as ‘classical’ macrophage activation, the result of which is the so-called classically-activated, or M1, macrophage (Fig. 11.11).
Macrophages require two main signals for classical activation, and effector TH1 cells can deliver both. One signal is the cytokine IFN-γ; the other, CD40L, sensitizes the macrophage to respond to IFN-γ (see Fig. 11.10). TH1 cells also secrete lymphotoxin, which can substitute for CD40 ligand in M1 macrophage activation. The M1 macrophage is a potent antimicrobial effector cell. Phagosomes fuse with lysosomes, and microbicidal reactive oxygen and
Fig. 11.11 Macrophages activated by TH1 cells undergo changes that greatly increase their antimicrobial effectiveness and amplify the immune response.