Fig. 9.35 The development of CD4 T-cell subsets can be manipulated by altering the cytokines acting during the early stages of infection. elimination of infection with the intracellular protozoan parasite Leishmania major requires a Th1 response, because IFn-γ is needed to activate the macrophages that provide protection. BaLB/c mice are normally susceptible to L. major because they generate a Th2 response to the pathogen. This is because they produce IL-4 early during infection and this induces naive T cells to develop into the Th2 lineage (see the text). Treatment of BaLB/c mice with neutralizing anti-IL-4 antibodies at the beginning of infection inhibits this IL-4 and prevents the diversion of naive T cells toward the Th2 lineage; these mice develop a protective Th1 response.
controls the differentiation of induced Treg cells and TH17 cells, respectively, in the intestinal mucosa-associated lymphoid tissues (MALT).
CD4 T cells that lack FoxP3 expression but produce immunosuppressive cytokines characteristic of Treg cells have also been described. One such population, referred to as TR1 cells, has been defined largely by their production of IL-10, but absence of expression of FoxP3. However, we now recognize that many different cells, including TH1, TH2, TH17, and B cells, can produce IL-10 under certain circumstances, such as during chronic responses to persistent antigen. Therefore, it is uncertain whether TR1 cells represent a distinct subset of T cells, and if so, whether they have unique functions in immune regulation.
Summary.
The crucial first step in adaptive immunity is the activation, or priming, of naive antigen-specific T cells by antigen-presenting cells within the lymphoid tissues through which they constantly circulate. The most distinctive feature of antigen-presenting cells is the expression of cell-surface co-stimulatory molecules, of which the B7 molecules are the most important. Naive T cells will respond to antigen only when the antigen-presenting cell presents both a specific antigen to the T-cell receptor and a B7 molecule to CD28 on the T cell. This dual requirement for both receptor ligation and co-stimulation by the same antigen-presenting cell helps to prevent naive T cells from responding to self antigens on tissue cells, which lack co-stimulatory activity.
Activation of naive T cells leads to their proliferation and differentiation into effector T cells, the critical event in most adaptive immune responses. Various combinations of cytokines regulate the type of effector T cell that develops in response to antigen. In turn, the cytokines present during primary T-cell activation are influenced by the innate immune system. Once an expanded clone of T cells acquires effector function, its progeny can act on any target cell that displays antigen on its surface. Effector T cells have a variety of functions. CD8 cytotoxic T cells recognize virus-infected cells and kill them. TH1 effector cells promote the activation of macrophages to enhance their killing of intracellular pathogens. TH2 cells promote mucosal barrier immunity against pathogens, such as helminths, requiring the effector activities of cells such as eosinophils and mast cells for their elimination. The elimination of certain types of bacteria and fungi is orchestrated by TH17 cells, particularly at barrier sites, where they recruit neutrophils to sites of infection and promote the production of antimicrobial peptides by epithelial cells. TFH cells are specialized for interactions with B cells and localization to the B-cell follicle and germinal centers, where they provide help for antibody production and isotype switching. Regulatory CD4 T-cell subsets restrain the immune response by preventing the activation of self-reactive naive T cells by antigen-presenting cells and producing inhibitory cytokines that limit the effector responses of other T-cell subsets.
General properties of effector T cells and their cytokines.