than CD28, but its effect is to inhibit, rather than activate, the T cell (Fig. 9.25). CTLA-4 does not contain an ITIM motif, and it is suggested to inhibit T-cell activation by competing with CD28 for interaction with B7 molecules expressed by antigen-presenting cells. Activation of naive T cells induces the surface expression of CTLA-4, making activated T cells less sensitive than naive T cells to stimulation by the antigen-presenting cell, thereby restricting IL-2 production. Thus, binding of CTLA-4 to B7 molecules is essential for limiting the proliferative response of activated T cells to antigen and B7. This was confirmed by producing mice with a disrupted CTLA-4 gene; such mice develop a fatal disorder characterized by a massive overgrowth of lymphocytes. Antibodies that block CTLA-4 from binding to B7 molecules markedly increase T cell-dependent immune responses.
Several TNF-family molecules also deliver co-stimulatory signals. These all seem to function by activating NFκB through a TRAF-dependent pathway (see Section 7-23). The binding of CD70 on dendritic cells to its constitutively expressed CD27 receptor on naive T cells delivers a potent co-stimulatory signal to T cells early in the activation process. The receptor CD40 on dendritic cells binds to CD40 ligand expressed on T cells, initiating two-way signaling that transmits activating signals to the T cell and also induces the dendritic cell to express increased B7, thus stimulating further T-cell proliferation. The role of the CD40–CD40 ligand pair in sustaining a T-cell response is demonstrated in mice lacking CD40 ligand; when these mice are immunized, the clonal expansion of responding T cells is curtailed at an early stage. The T-cell molecule 4-1BB (CD137) and its ligand 4-1BBL, which is expressed on activated dendritic cells, macrophages, and B cells, make up another pair of TNF-family co-stimulators. The effects of this interaction are also bidirectional, with both the T cell and the antigen-presenting cell receiving activating signals; this type of interaction is sometimes referred to as the T-cell:antigen-presenting cell dialog. Another co-stimulatory receptor and its ligand, OX40 and OX40L, are expressed on activated T cells and dendritic cells, respectively. Mice deficient in OX40 show reduced CD4 T-cell proliferation in response to viral infection, indicating that OX40 has a role in sustaining ongoing T-cell responses by enhancing T-cell survival and proliferation.
9-18 Proliferating T cells differentiate into effector T cells that do not require co-stimulation to act.
During the 4–5 days of rapid cell division that follow naive T-cell activation, T cells differentiate into effector T cells that acquire the ability to synthesize molecules required for their specialized helper or cytotoxic functions when they re-encounter their specific antigen. Effector T cells undergo additional changes that distinguish them from naive T cells. One of the most important is in their activation requirements: once a T cell has differentiated into an effector cell, encounter with its specific antigen results in immune attack without the need for co-stimulation (Fig. 9.26). This distinction is particularly easy to understand for CD8 cytotoxic T cells, which must be able to act on any cell infected with a virus, whether or not the infected cell can express co-stimulatory molecules. However, this feature is also important for the effector function of CD4 cells, as effector CD4 T cells must be able to activate B cells and macrophages that have taken up antigen even if these cells are not initially expressing co-stimulatory molecules.