TH1 cells help to eradicate infections by microbes that can survive or replicate within macrophages. Examples include certain viruses, protozoans, and intracellular bacteria, such as the mycobacteria that cause tuberculosis and leprosy. These bacteria are phagocytosed by macrophages in the usual way but can evade the intracellular killing mechanisms described in Chapter 3. If a TH1 cell recognizes bacterial antigens displayed on the surface of an infected macrophage, it will activate the macrophage further through the release of IFN-γ, which enhances the macrophage’s microbicidal activity to kill ingested bacteria. Type 1 responses also promote B-cell class switching that favors production of opsonizing IgG antibodies, such as IgG2a in mouse. We shall describe the macrophage-activating functions of TH1 cells in more detail in Chapter 11.
TH2 cells help to control infections by extracellular parasites, particularly helminths, by promoting responses mediated by eosinophils, mast cells, and IgE. In particular, cytokines produced as part of a type 2 response are required for class switching of B cells to produce IgE, the primary role of which is to fight parasitic infections. IgE is also the antibody responsible for allergies and asthma, making TH2 differentiation of additional medical interest.
The third major effector subset of CD4 T cells is TH17. TH17 cells are typically induced in response to extracellular bacteria and fungi, and amplify neutrophilic responses that help to clear such pathogens (see Fig. 9.30). TH17, or type  3, responses also promote B-cell class switching to opsonizing IgG2 and IgG3 antibodies. Cytokines produced by TH17 cells, including IL-17 and IL-22, are also important in activating barrier epithelial cells in the gastrointestinal, respiratory, and urogenital tracts and the skin, to produce antimicrobial peptides that resist microbial invasion.
In contrast to TH1, TH2, or TH17 cells, TFH cells contribute to the eradication of most classes of pathogens through their unique role in providing help to B cells to promote germinal center responses—irrespective of the pattern of immune response with which they are associated. Thus, TFH cells are elicited in the context of either type 1, type 2, or type 3 responses, where they play a central role in the development of distinct patterns of class-switched antibodies. TFH cells are identified mainly by their expression of certain markers, such as CXCR5 and PD-1, and their localization to lymphoid follicles.
Prior to the discovery of TFH cells, a point of controversy had been the role of CD4 T effector subsets in providing B-cell help. Although it was originally implied that this was primarily the function of TH2 cells, it is now thought that the TFH cell, rather than TH1, TH2, or TH17 cells, is the primary effector T cell that provides B-cell help for high-affinity antibody production in lymphoid follicles. Nevertheless, TFH cells develop as a component of type 1, 2, or 3 responses, and share production of some of the same lineage-defining cytokines of TH1, TH2, and TH17 cells to drive the differentiation of naive B cells to alternative patterns of isotype switching. This explains how, in the course of an infection, B cells can receive help to switch to IgE through the presence of ‘TH2’ cytokines, or switch to other isotypes such as IgG2a through the presence of ‘TH1’ cytokines. Thus, while the developmental relationship of TFH to other CD4 subsets is still a matter of active research, TFH cells appear to represent a distinct branch of effector T cells that remain within the lymphoid tissues and are specialized for providing B-cell help. We will return to the helper functions of TFH cells in more detail in Chapters 10 and 11.