Differentiation of CD4 T Cells into TH1 TH2 and Th17 Effector Cells

Effector cells of the CD4+ lineage are characterized by their ability to express surface molecules and to secrete cytokines that activate other cells (B lymphocytes, macrophages, and dendritic cells). Whereas naive CD4+ T cells produce mostly IL-2 on activation, effector CD4+ T

cells are capable of producing a large number and variety of cytokines that have diverse biologic activities.

There are three distinct subsets of CD4+ T cells, called Th1, Th2, and TH17, that function in host defense against different types of infectious pathogens and are involved in different types of tissue injury in immunologic diseases (Fig. 9-13). A fourth population, called follicular helper T cells, is important in antibody responses and is described in Chapter 11. Regulatory T cells are another distinct population of CD4+ T cells. Their function is to control immune reactions to self and foreign antigens, and they are described in Chapter 14 in the context of immunologic tolerance. Although these subsets are identifiable in immune reactions (and can often be generated in cell culture), many effector CD4+ T cells produce various combinations of cytokines or only some of the cytokines characteristic of a particular subset and are not readily classifiable into separable populations. Whether these populations with mixed or limited cytokine patterns are intermediates in the development of the polarized effector cells or are themselves fixed populations is not known. It is also clear that some of these differentiated T cells may convert from one population into another by changes in activation conditions. The extent and significance of such "plasticity" are topics of active research.

Properties of TH1, TH2, and TH17 Subsets

Elucidation of the development, properties, and functions of subsets of effector CD4+ T cells has been one of the most impressive accomplishments of immunology research. It was appreciated many years ago that host responses to different infections varied greatly, as did the reactions in different immunologic diseases. For instance, the immune reaction to intracellular bacteria like Mycobacterium tuberculosis is dominated by activated macrophages, whereas the reaction to helminthic parasites

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FIGURE 9-13 Properties of TH1, TH2, and TH17 subsets of CD4+ helper T cells. Naive CD4+ T cells may differentiate into distinct subsets of effector cells in response to antigen, costimulators, and cytokines. The columns to the right list the major differences between the best-defined subsets.

consists of IgE antibody production and the activation of eosinophils. Along the same lines, in many chronic autoimmune diseases, tissue damage is caused by inflammation with accumulation of neutrophils, macrophages, and T cells, whereas in allergic disorders, the lesions contain abundant eosinophils along with other leukocytes. The realization that all these phenotypically diverse immunologic reactions are dependent on CD4+ T cells raised an obvious question: How can the same CD4+ cells elicit such different responses? The answer, as we now know, is that CD4+ T cells consist of subsets of effector cells that produce distinct sets of cytokines, elicit quite different reactions, and are involved in host defense against different microbes as well as in distinct types of immunologic diseases. The first subsets that were discovered were called Th1 and TH2 (so named because they were the first two subsets identified). It was subsequently found that some inflammatory diseases that were thought to be caused by TH1-mediated reactions were clearly not dependent on this type of T cell, and this realization led to the discovery of TH17 cells (called TH17 because their characteristic cytokine is IL-17). In the next section, we describe the properties of these subsets and how they develop from naive T cells. We will return to their cyto-kine products, effector functions, and roles in cellmediated immunity in Chapter 10.

The defining characteristics of differentiated subsets of effector cells are the cytokines they produce, the transcription factors they express, and epigenetic changes in cytokine gene loci. These characteristics of TH1, TH2, and TH17 cells are described below.

The signature cytokines produced by the major CD4+ T cell subsets are IFN-yfor TH1 cells; IL-4, IL-5, and IL-13 for Th2 cells; and IL-17 and IL-22 for TH17 cells (see Fig. 9-13). The cytokines produced by these T cell subsets determine their effector functions and roles in diseases. The cytokines also participate in the development and expansion of the respective subsets (described later). In addition, these subsets of T cells differ in the expression of adhesion molecules and receptors for chemokines and other cytokines, which are involved in the migration of distinct subsets to different tissues (see Chapter 10).

Development of TH1, TH2, and TH17 Subsets

Differentiated TH1, TH2, and TH17 cells all develop from naive CD4+ T lymphocytes, mainly in response to cytokines present early during immune responses, and differentiation involves transcriptional activation and epigenetic modification of cytokine genes. The process of differentiation, which is sometimes referred to as polarization of T cells, can be divided into induction, stable commitment, and amplification (Fig. 9-14). Cytokines act on antigen-stimulated T cells to induce the transcription of cytokine genes that are characteristic of differentiation toward each subset. With continued activation, epigen-etic changes occur so that the genes encoding that subset's cytokines are more accessible for activation, and genes that encode cytokines not produced by that subset are rendered inaccessible. Because of these changes, the differentiating T cell becomes progressively committed to one specific pathway. Cytokines produced by any given subset promote the development of this subset and inhibit differentiation toward other CD4+ subpopulations. Thus, positive and negative feedback loops contribute to the generation of an increasingly polarized population of effector cells.

There are several important general features of T cell subset differentiation.

• The cytokines that drive the development of CD4+ T cell subsets are produced by APCs (primarily dendritic cells and macrophages) and other immune cells (such as NK cells and basophils or mast cells) present at the site of the immune response. Dendritic cells that encounter

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FIGURE 9-14 Development of TH1, TH2, and TH17 subsets.

Cytokines produced early in the innate or adaptive immune response to microbes promote the differentiation of naive CD4+ T cells into TH1, TH2, or Th17 cells by activating transcription factors that stimulate production of the cytokines of each subset (the early induction step). Progressive activation leads to stable changes in the expressed genes (commitment), and cytokines promote the development of each population and suppress the development of the other subsets (amplification). These principles apply to all three major subsets of CD4+ effector T cells.

microbes and display microbial antigens are activated to produce cytokines (as well as costimulators, described earlier) as part of innate immune responses to the microbes (see Chapter 4). Different microbes may stimulate dendritic cells to produce distinct sets of cytokines, perhaps because the microbes are recognized by different microbial sensors in the cells. Other cells of innate immunity, such as NK cells and mast cells, also produce cytokines that influence the pattern of T cell subset development.

• Stimuli other than cytokines may also influence the pattern of helper T cell differentiation. Some studies indicate that different subsets of dendritic cells selectively promote either TH1 or TH2 differentiation; the same principle may be true for TH17 cells. In addition, the genetic makeup of the host is an important determinant of the pattern of T cell differentiation. Inbred mice of some strains develop TH2 responses to the same microbes that stimulate TH1 differentiation in most other strains. Strains of mice that develop TH2-dominant responses are susceptible to infections by intracellular microbes (see Chapter 15).

• The distinct cytokine profiles of differentiated cell populations are controlled by particular transcription factors that activate cytokine gene transcription and by chromatin modifications affecting cytokine gene loci. The transcription factors are themselves activated or induced by cytokines as well as by antigen receptor stimuli. 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 (changes in methylation and acetylation) and consequent chromatin remodeling events, so that these loci are "accessible" and in an "open" chromatin configuration, whereas the loci for other cytokines (those not produced by that subset) are in an inaccessible chro-matin state. These epigenetic changes ensure that each subset can produce only its characteristic collection of cytokines. It is likely that epigenetic changes in cyto-kine gene loci correlate with stable phenotypes, and before these changes are established, the subsets may be plastic and convertible.

• 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-y secreted by TH1 cells promotes further TH1 differentiation and inhibits the generation of TH2 and TH17 cells. Similarly, IL-4 produced by TH2 cells promotes TH2

differentiation, and IL-21 produced by TH17 cells enhances TH17 differentiation. Thus, each subset amplifies itself and may inhibit the other subsets. For this reason, 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 in chronic exposure to environmental antigens, when the immune stimulation is prolonged. • Differentiation of each subset is induced by the types of microbes which that subset is best able to combat. For instance, the development of TH1 cells from antigen-stimulated T cells is driven by intracel-lular microbes, against which the principal defense is Th1 mediated. Conversely, the immune system responds to helminthic parasites by the development of TH2 cells, and the cytokines produced by these cells are critical for combating helminths. Similarly, TH17 responses are induced by some bacteria and fungi and are most effective at defending against these microbes. 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.

With this background, we proceed to a description of the signals for and mechanisms of development of each subset.

Th1 Differentiation

Th1 differentiation is driven mainly by the cytokines IL-12 and IFN-y and occurs in response to microbes that activate dendritic cells, macrophages, and NK cells (Fig. 9-15). The differentiation of antigen-activated CD4+ T cells to TH1 effectors is stimulated by many intracellular bacteria, such as Listeria and mycobacteria, and by some parasites, such as Leishmania, all of which infect dendritic cells and macrophages. It is also stimulated by viruses and by protein antigens administered with strong adjuvants. A common feature of these infections and immunization conditions is that they elicit innate immune reactions that are associated with the production of certain cytokines, including IL-12, IL-18, and type I interferons. All these cytokines promote TH1 development; of these, IL-12 is probably the most potent. Knockout mice lacking IL-12 are extremely susceptible to infections with intracellular microbes. IL-18 synergizes with IL-12, and type I interferons may be important for TH1 differentiation in response to viral infections, especially in humans. Other microbes stimulate NK cells to produce IFN-y, which is itself a strong TH1-inducing cytokine and also acts on dendritic cells and macrophages to induce more IL-12 secretion. Once TH1 cells have developed, they secrete IFN-y, which promotes more TH1 differentiation and thus strongly amplifies the reaction. In addition, IFN-y inhibits the differentiation of naive CD4+ T cells to the TH2 and TH17 subsets, thus promoting the polarization of the immune response in one direction. T cells may further enhance cytokine production by dendritic cells and macrophages, by virtue of CD40 ligand (CD40L) on activated

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