TH2 and TH17 cells display different patterns of inflammatory chemokine receptors, some of which, like those expressed by TH1 cells, are shared with the myelomonocytic cells with which they interact in inflamed tissues (see Figs. 11.8 and 11.9). The shared expression pattern of chemokine receptors by innate and adaptive effector cells represents an important mechanism for the spatiotemporal coordination and integration of immune effector modules in response to different types of pathogen (see Fig. 11.8). Thus, the local release of cytokines and chemokines at the site of infection has far-reaching consequences. In addition to recruiting granulocytes and monocytes, which constitutively express their specific complement of chemokine receptors while in circulation, changes induced in the blood vessel walls also enable newly generated effector T lymphocytes to enter infected tissues. Once in the tissue, recruited T cells produce T helper cell type–specific cytokines that further increase specific chemokine production by innate immune cells in an additional feed-forward mechanism that results in further effector T cell and innate effector cell trafficking into the tissue. Because the cytokines that differentially drive local production of effector module-specific chemokines are similarly produced by ILCs, this represents another major function of ILCs in coordinating the early polarization of pathogen-specific responses.
11-4 Pathogen-specific effector T cells are enriched at sites of infection as adaptive immunity progresses.
In the early stage of the adaptive immune response, only a minority of the effector T cells that enter infected tissues will be specific for pathogen. This is because activation of the endothelium of local blood vessels by inflammatory cytokines induces expression of selectins, integrin ligands, and chemokines that can recruit any circulating effector or memory T cell that expresses the appropriate trafficking receptors, irrespective of its antigenic specificity. However, specificity of the reaction is rapidly increased as the number of pathogen-specific T cells increases and recognition of antigen within the inflamed tissue retains them there. Although the precise mechanisms controlling retention of antigen-activated effector T cells in the inflamed tissue are not entirely understood, it is thought that the same mechanisms that retain antigen-activated naive T cells within secondary lymphoid tissues during effector
Fig. 11.9 The expression of adhesion and chemokine receptors is altered during effector T cell differentiation.
During a primary immune response, specific cytokines derived from the innate immune system (indicated along the three diverging arrows) and unique master transcription factors (T-bet, GATA3, and RORγt) direct naive CD4 T cells to differentiate into TH1, TH2, or TH17 effector cells. Effector T cells of each subset lose expression of L-selectin (CD62L) and CCR7, and express characteristic chemokine receptors.
Fig. 11.10 TH1 cells activate macrophages to become highly microbicidal. When an effector TH1 cell specific for a bacterial peptide contacts an infected macrophage, the T cell is induced to secrete the macrophage-activating factor IFN-γ and to express CD40 ligand. Together these newly synthesized TH1 proteins activate the macrophage.
T-cell development might be at play. This includes a role for the S1P pathway, although other chemokine signals may participate. By the peak of an adaptive immune response, after several days of clonal expansion and differentiation, a large fraction of the recruited T cells will be specific for the infecting pathogen.