It was appreciated many years ago that host responses to different infections vary greatly, as do the reactions in different immunologic diseases. For instance, the immune reaction to bacteria that survive within phagocytes, like Mycobacterium tuberculosis, is dominated by activated macrophages, whereas the reaction to helminthic parasites consists of the production of immunoglobulin E (IgE) antibody and the activation of eosinophils. Furthermore, in many chronic autoimmune diseases, tis sue damage is caused by inflammation with accumulation of neutrophils and macrophages, whereas in allergic disorders, the lesions contain abundant eosinophils along with other leukocytes. The realization that all of these phenotypically diverse immunologic reactions are dependent on CD4+ T cells raises 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, stimulate quite different immune reactions, and are involved in host defense against different microbes, as well as in distinct types of immunologic diseases. The first two subsets that were discovered were called types 1 and 2 helper T cells, or Th1 and Th2. The Th17 subset, so named because its characteristic cytokine is interleukin-17 (IL-17), was identified many years later as the T cells responsible for some CD4+ T cell mediated inflammatory reactions that could not be attributed to the Th1 and Th2 subsets.
The defining characteristics of differentiated subsets of effector cells are the cytokines they produce, which is related to the transcription factors they express. The transcription factors are responsible for production of different cytokines by these subsets as well as expression of different chemokine receptors and other proteins. These characteristics of each subset are described in the following section.
The signature cytokines produced by the major CD4+ T-cell subsets are interferon (IFN)-γ for Th1 cells; IL-4, IL-5, and IL-13 for Th2 cells; and IL-17 and IL-22 for Th17 cells (see Fig. 1). The cytokines produced by these T-cell sub sets determine their effector functions and roles in diseases. Some of the cytokines made by each subset also stimulate the development and expansion of that subset and inhibit differentiation of the other Th subsets, thus contributing to amplification of each type of helper T-cell response, a process called polarization (discussed later). The production of distinct sets of cytokines is initiated by the expression of subset-specific transcription factors and is sustained by epigenetic modifications of specific cytokine gene loci. These mechanisms are described later.
Fig1. Properties of the major subsets of CD4+ helper T cells. Naive CD4+ T cells may differentiate into distinct subsets of effector cells in response to antigens, costimulators, and cytokines. Each subset acts mainly on another cell of the immune system (referred to as target cells) and serves different functions and roles in disease. T follicular helper (Tfh) cells are discussed in Chapter 12. IFN, Interferon; IL, interleukin.
Th1, Th2, and Th17 cells have distinct patterns of homing, in large part because they express different chemokine receptors and adhesion molecules that direct them to migrate into different sites. We discussed the control of lymphocyte migration in Chapter 3. Th1, but not Th2, cells express high levels of the chemokine receptors CXCR3 and CCR5, which bind to chemokines produced in tissues during innate immune responses. Therefore, Th1 cells tend to be abundant at sites of infection where the infectious agents trigger strong innate immune reactions; these agents include many bacteria and viruses. Th1 cells also express high levels of ligands for E-selectin and P-selectin, which assist in the migration of these cells to sites of strong inflammation (where the selectins are expressed on the endothelium). In contrast, Th2 cells express the chemokine receptors CCR3, CCR4, and CCR8, which recognize chemokines that are highly expressed at sites of helminthic infection or allergic reactions, particularly in mucosal tissues, and so Th2 cells tend to migrate to these tissues. Th17 cells express CCR6, which binds the chemokine CCL20, which is produced by various tissue cells and macrophages in some bacterial and fungal infections.
Although for many years it was thought that Th1 and Th2 cells help B lymphocytes to produce different antibodies, it is now clear that, as stated earlier, most of these differentiated effector cells leave the lymphoid organs where they are generated and migrate to peripheral sites of infection. Antibody responses develop mostly in secondary lymphoid organs, and particularly in germinal centers, where antigen-specific B and T cells interact. The CD4+ helper T cells that remain in secondary lymphoid organs to help B lymphocytes are not classical Th1, Th2, or Th17 cells, but Tfh cells that make some of the same cytokines that Th subsets do.
Various inflammatory diseases are caused by excessive reactions of different helper T-cell subsets. In general, Th1 and Th17 cells play prominent roles in autoimmune diseases associated with inflammation, whereas allergic reactions are dominated by Th2 cells.
The identification of Th1, Th2, and Th17 subsets has pro vided many insights into lymphocyte responses. However, there are some caveats with the idea that all effector CD4+ T cells can be classified into these subsets based on defined criteria. Many CD4+ effector T cells produce combinations of cytokines or only some of the cytokines characteristic of a particular subset and are not readily classifiable into separable populations. For instance, in some inflammatory reactions, there may be individual T cells that produce both IFN-γ (characteristic of Th1 cells) and IL-17 (typical of Th17 cells). Conversely, T cells may produce cytokines that are not characteristic of any of the three subsets (such as IL-9) or only some of the cytokines produced by a particular subset. These restricted cytokine profiles have led to an expanding nomenclature describing these populations (such as Th9, Th22, and so on). It is not known whether cells with mixed or limited cytokine patterns are intermediates in the development of the classical polarized effector cells or are themselves fixed populations.
It is also clear that some of these effector T cells may convert from one cytokine profile to another in response to changes in activation conditions. The extent and significance of plasticity or stability of differentiated effector T cells remain topics of research.
Although CD4+ effector T cells are the main sources of many cytokines in protective and pathologic adaptive immune responses, the same cytokines may be produced by other cell types, such as γδ T cells and innate lymphoid cells (ILCs). As we discussed in Chapter 4, ILCs are classified into groups that produce many of the same cytokines as subsets of effector CD4+ T cells do. For this reason, the concept has evolved that cytokine dependent host defense and pathologic reactions are mediated by the coordinated actions of ILCs early in the response and effector CD4+ T cells late. Such responses may be viewed as types of immunity; type 1 immunity relies on ILC1, NK, and Th1 cells; type 2 immunity relies on ILC2 and Th2 cells; and type 3 immunity relies on ILC3 and Th17 cells.
