Activated macrophages increase their expression of CD40 and of TNF receptors, and are stimulated to secrete TNF-α. This autocrine stimulus synergizes with IFN-γ secreted by TH1 cells to induce classical, or M1, macrophage activation characterized by the production of nitric oxide (NO) and superoxide (O2–). The macrophage also upregulates its B7 molecules in response to binding to CD40 ligand on the T cell, and increases its expression of MHC class II molecules in response to IFN-γ, thus allowing further activation of resting CD4 T cells.
nitrogen species are generated, as described in Section 3-2. When TH1 cells stimulate macrophages through these molecules, the M1 macrophage also secretes TNF-α, further stimulating macrophages through the TNFR-I, the same receptor activated by LT-α. TNF receptor signalling seems to be required to maintain the viability of the macrophage in this setting; in mice lacking TNFR-I (see Section 9-28), infection by Mycobacterium avium, an opportunistic intracellular pathogen that does not normally cause disease, leads to excessive apoptosis of macrophages that results in the release and dissemination of the pathogen before it can be killed within the infected macrophage. CD8 T cells also produce IFN-γ and can activate macrophages presenting antigens derived from cytosolic proteins on MHC class I molecules. Macrophages can also be made more sensitive to IFN-γ by very small amounts of bacterial LPS, and this latter pathway may be particularly important when CD8 T cells are the primary source of the IFN-γ.
In addition to increased intracellular killing, TH1 cells induce other changes in macrophages that help to amplify the adaptive immune response against intracellular pathogens. These changes include an increase in the number of MHC class II molecules, B7 molecules, CD40, and TNF receptors on the M1 macrophage surface (see Figs. 11.10 and 11.11), making the cell more effective at presenting antigen to T cells, and more responsive to CD40 ligand and TNF-α. In addition, M1 macrophages secrete IL-12, which increases the amount of IFN-γ produced by ILC1s and TH1 cells. This also promotes the differentiation of activated naive CD4 T cells into TH1 effector cells, and naive CD8 T cells into cytotoxic effectors (see Sections 9-20 and 9-18).
Another important function of TH1 cells is the recruitment of additional phagocytic cells to sites of infection. TH1 cells recruit macrophages by two mechanisms (Fig. 11.12). First, they make the hematopoietic growth factors IL-3 and GM-CSF, which stimulate the production of new monocytes in the bone marrow. Second, the TNF-α and lymphotoxin secreted by TH1 cells at sites of infection change the surface properties of endothelial cells so that monocytes adhere to them. Chemokines such as CCL2, which are induced by TH1 cells at inflammatory sites, direct the migration of monocytes through the vascular endothelium and into the infected tissue, where they differentiate into macrophages (see Section 3-17). Cytokines and chemokines secreted by M1 macrophages themselves are also important in recruiting other monocytes to sites of infection. Collectively, these TH1-mediated effects provide a positive feedback loop that amplifies and sustains type 1 responses until the pathogen is controlled or eliminated.