Differentiated Th1, Th2, and Th17 cells all develop from naive CD4+ T lymphocytes, mainly in response to cytokines present early during immune responses. The process of effector T-cell differentiation involves multiple steps. Signals that T cells receive from APCs and other cells at the site of the immune response initiate the conversion of antigen-stimulated T cells to effector cells. Differentiating effector cells become progressively committed to a particular cytokine production profile, and cytokines amplify these differentiation pathways. The net result is the progressive accumulation of T-cell populations that produce distinct sets of cytokines.
There are several important general features of T-cell subset differentiation.
• The cytokines that drive the differentiation of CD4+ T-cell subsets are produced by APCs (primarily dendritic cells [DCs] and macrophages) and other immune cells (such as NK cells and mast cells) present in the lymphoid organ where the immune response is initiated. DCs that encounter microbes and display microbial antigens are activated to produce cytokines (as well as costimulators) as part of innate immune responses to the microbes. Different microbes may stimulate DCs to produce distinct sets of cytokines, perhaps because the microbes activate different DC populations or are recognized by different microbial sensors in the cells. Other cells of innate immunity, such as NK cells, ILCs, and mast cells, also produce cytokines that promote the development of antigen-stimulated T cells into different effector subsets.
• Stimuli other than cytokines influence the pattern of helper T-cell differentiation. Experimental evidence indicates that the affinity of the T-cell receptor (TCR) for antigen, the amount of antigen, and the nature of the APC all determine the dominant subset that develops after antigen recognition. But the contribution of these factors to the differentiation of effector subsets in most immune responses is not clear. The genetic makeup of the host is another important determinant of the pattern of T-cell differentiation. Some inbred strains of mice mount Th2 responses to the same microbes that stimulate Th1 differentiation in most other strains. Strains of mice that make Th2-dominant responses are susceptible to infections by intracellular microbes (see Chapter 16). It is possible, but not proven, that people differ in their pro pensity to generate Th1, Th2, or Th17 responses based on inherited genes.
• The distinct cytokine profiles of differentiated cell populations are controlled by particular transcription factors that activate cytokine gene expression and by chromatin modifications affecting accessibility of these factors to the promoters and regulatory elements of cytokine genes. The transcription factors are activated or induced by signals from the TCR, innate immune receptors, costimulators, and cytokine receptors. Each subset expresses its own characteristic set of transcription factors. As the subsets become increasingly polarized, the gene loci encoding that subset’s signature cytokines undergo histone modifications (such as changes in methylation and acetylation) and other chromatin remodeling events, so that these loci remain accessible to RNA polymerase and transcription factors, whereas the loci for other cytokines (those not produced by that subset) are in an inaccessible chromatin state. Thus, the cytokine genes characteristic of a particular subset become stabilized in an antigen responsive state, whereas genes that encode cytokines not produced by that subset remain inactive. These epigenetic changes are inherited in the progeny of proliferating cells, thus ensuring that the effector T cells become stably commit ted to producing a particular set of cytokines.
• Each subset of differentiated effector cells produces cytokines that promote its own development and may suppress the development of the other subsets. This feature of T-cell subset development provides a powerful amplification mechanism. For instance, IFN-γ secreted by Th1 cells stimulates further Th1 differentiation and inhibits the generation of Th2 and Th17 cells. Similarly, IL-4 produced by Th2 cells pro motes Th2 differentiation. Thus, once an immune response develops along one effector pathway, it becomes increasingly polarized in that direction, and the most extreme polarization is seen in chronic infections or upon chronic exposure to environmental antigens, when the immune stimulation is prolonged.
• Differentiation of each subset is induced by the types of microbes that the subset is best able to combat. For instance, the development of Th1 cells is driven by intracellular microbes, against which the principal defense is Th1 mediated. By contrast, the immune system responds to helminthic parasites by the development of Th2 cells, and the cytokines produced by these cells are important for combating helminths. Similarly, Th17 responses are induced by some bacteria and fungi and are most effective at defending against these pathogens. The generation and effector functions of these differentiated T cells are an excellent illustration of the concept of specialization of adaptive immunity, which refers to the ability of the immune system to respond to different microbes in ways that are optimal for combating those microbes.
