Some infectious agents, such as the intracellular Gram-positive bacterium Listeria monocytogenes and the Gram-negative bacterium Burkholderia pseudomallei, appear to be able to directly license dendritic cells to induce primary CD8 T-cell responses without requirement for CD4 T-cell help (Fig. 11.21). Primary CD8 T-cell responses to L. monocytogenes were examined in mice that were genetically deficient in MHC class II molecules and thus lacked CD4 T cells (see Section 11-23). The numbers of CD8 T cells specific for a particular antigen expressed by the pathogen were measured by using tetrameric peptide:MHC complexes, or peptide:MHC tetramers (see Appendix I, Section A-24), which can identify CD4 or CD8 T cells on the basis of the antigenic specificity of their T-cell receptors. On day 7 of infection, wild-type mice and mice lacking CD4 T cells showed equivalent expansion, and
Fig. 11.21 Naive CD8 T cells can be activated directly by potent antigen-presenting cells through their T-cell receptor or through the action of cytokines. Left panels: naive CD8 T cells that encounter peptide:MHC class I complexes on the surface of dendritic cells expressing high levels of co-stimulatory molecules as a result of the inflammatory environment produced by some pathogens (upper left panel) are activated to proliferate in response, eventually differentiating into cytotoxic CD8 T cells (lower left panel). Right panels: activated dendritic cells also produce the cytokines IL-12 and IL-18, whose combined effect on CD8 T cells rapidly induces the production of IFN-γ (upper right panel). This activates macrophages for the destruction of intracellular bacteria and can promote antiviral responses in other cells (lower right panel).
equivalent cytotoxic capacity, of pathogen-specific CD8 T cells. Mice lacking CD4 T cells cleared the initial infection by L. monocytogenes as effectively as wild-type mice. These experiments clearly show that protective responses can be generated by pathogen-specific CD8 T cells without CD4 T-cell help. However, as we will see later, the nature of the CD8 memory response is different and is diminished in the absence of CD4 T-cell help.
Naive CD8 T cells can also undergo ‘bystander’ activation by IL-12 and IL-18 to produce IFN-γ very early during infection (see Fig. 11.21). Mice infected with
L. monocytogenes or B. pseudomallei rapidly produce a strong IFN-γ response, which is essential for their survival. The source of this IFN-γ seems to be both NK cells and naive CD8 T cells, which begin to secrete it within the first few hours after infection. This is believed to be too soon for any significant expansion of pathogen-specific CD8 T cells, which would initially be too rare to contribute in an antigen-specific manner. The production of IFN-γ by both NK and CD8 T cells at this early time can be blocked experimentally by antibodies against IL-12 and IL-18, suggesting that these cytokines are responsible. These experiments indicate that naive CD8 T cells can contribute nonspecifically in a kind of innate defense, one not requiring CD4 T cells, in response to early signals of infection.
11-16 Resolution of an infection is accompanied by the death of most of the effector cells and the generation of memory cells.