Cytotoxic T cells are also required for the destruction of cells infected with some intracellular bacterial pathogens, such as Rickettsia (the causative agent of typhus) or Listeria, which can escape from phagocytic vesicles to avoid the killing mechanisms of activated macrophages. In contrast, mycobacteria, which resist phagolysosomal killing and can live inside macrophage vesicles, are mainly kept in check by TH1 cells, which activate infected macrophages to kill the bacteria. Nevertheless, antibodies are induced in these infections and can contribute to pathogen killing when organisms are released from dying phagocytes, and are important in resistance to reinfection.
In many cases the most efficient protective immunity is mediated by neutralizing antibodies that can prevent pathogens from establishing an infection, and most of the established vaccines against acute childhood viral infections work primarily by inducing protective antibodies. Effective immunity against polio virus, for example, requires preexisting antibody, because the virus rapidly infects motor neurons and destroys them unless it is immediately neutralized by antibody and prevented from spreading within the body. In polio, specific IgA on mucosal epithelial surfaces also neutralizes the virus before it enters the tissues. Thus, protective immunity can involve effector mechanisms (IgA in this case) that do not operate in the elimination of the primary infection.
Fig. 11.20 Plasticity of CD4+ T-cell subsets. There is a hierarchy of stability of effector and regulatory CD4 T cells. Naive CD4+ T cells are multipotent, whereas TH1 and TH2 cells appear to be relatively stable, or at ‘ground state’; that is, they are highly resistant to transitioning into other effector cell phenotypes. iT cells and TH17 cells are less stable, and can transition into other subsets depending on prevailing cytokines. When acted on by IL-6 and IL-1, iT cells can transition into TH17 cells, or when acted on by IL-12 can become TH1 cells. TH17 cells acted on by IL-12 can transition into TH1 cells. Notably, the transitions of iT cells into TH17 cells, and TH17 cells into TH1 cells, appear to be unidirectional, or irreversible. Developing TH2 cells (left) repress expression of the inducible component of the IL-12 receptor (IL-12Rβ) and are unresponsive to IL-12; iTreg, TH17, and TH1 subsets (right) remain responsive to IL-12.
11-15 Primary CD8 T-cell responses to pathogens can occur in the absence of CD4 T-cell help.
Many CD8 T-cell responses are deficient in the absence of help from CD4 T cells (see Section 9-19). In such circumstances, CD4 T-cell help is required to activate dendritic cells for them to become able to stimulate a complete CD8 T-cell response, an activity that has been described as licensing of the antigen-presenting cell (see Section 9-10). Licensing involves the induction of co-stimulatory molecules such as B7, CD40, and 4-1BBL on the dendritic cell, which can then deliver signals that fully activate naive CD8 T cells (see Fig. 9.29). Licensing enforces a requirement for dual recognition of an antigen by the immune system by both CD4 and CD8 T cells, which provides a useful safeguard against autoimmunity. Dual recognition is also seen in the cooperation between T cells and B cells for antibody generation (see Chapter 10). However, not all CD8 T-cell responses require such help.