The full activation of T cells depends on the recognition of costimulators on APCs in addition to antigen (Fig. 1). We have previously referred to costimulators as second signals for T cell activation. The name costimulator derives from the fact that these molecules provide stimuli to T cells that function together with stimulation by antigen.

Fig1. Role of costimulation in T cell activation. Resting antigen-presenting cells (APCs), which have not been exposed to microbes or adjuvants, may present peptide antigens, but they do not express costimulators and are unable to activate naive T cells. T cells that recognize antigen without costimulation may die or become unresponsive (tolerant) to subsequent exposure to antigen. Microbes, as well as cytokines produced during innate immune responses to microbes, induce the expression of costimulators, such as B7 molecules, on the APCs. The B7 costimulators are recognized by the CD28 receptor on naive T cells, providing signal 2. In conjunction with antigen recognition (signal 1), this recognition initiates T cell responses. Activated APCs also produce cytokines that stimulate the differentiation of naive T cells into effector cells (not shown). IL, Interleukin.

The best-defined costimulators for T cells are two homologous proteins called B7-1 (CD80) and B7-2 (CD86), both of which are expressed on APCs and whose expression is increased when the APCs encounter microbes. These B7 proteins are recognized by a receptor called CD28, which is expressed on most T cells. Different members of the B7 and CD28 families serve to stimulate or inhibit immune responses (Fig. 2). The binding of CD28 on T cells to B7 on the APCs generates signals in the T cells that work together with signals generated by TCR recognition of antigen presented by MHC proteins on the same APCs. CD28-mediated signaling is essential for the responses of naive T cells; in the absence of CD28:B7 interactions, antigen recognition by the TCR is insufficient for initiating T cell responses. The requirement for costimulation ensures that naive T lymphocytes are activated maximally by microbial antigens and not by harmless foreign substances or by self antigens, because, as stated previously, microbes stimulate the expression of B7 costimulators on APCs.

Fig2. Proteins of the B7 and CD28 families. Ligands on APCs that are homologous to B7 bind to receptors on T cells that are homologous to CD28. Different ligand-receptor pairs serve distinct roles in immune responses. CD28 and ICOS are stimulatory receptors on T cells, and CTLA-4 and PD-1 are inhibitory receptors. Their functions are discussed in the text.

A protein called ICOS (inducible costimulator), which is homologous to CD28 and also expressed on T cells, plays an important role in the development and function of follicular helper T cells during germinal center responses .

Another set of molecules that participate in T cell responses are CD40 ligand (CD40L, or CD154) on activated T cells and CD40 on APCs. These molecules do not directly enhance T cell activation. Instead, CD40L expressed on an antigen-stimulated T cell binds to CD40 on APCs and activates the APCs to express more B7 costimulators and to secrete cytokines (e.g., IL-12) that enhance T cell differentiation. Thus, the CD40L-CD40 interaction promotes T cell activation by making APCs better at stimulating T cells. CD40L on effector CD4+ T cells also enhances activation of B cells and macrophages, as discussed later.

The role of costimulation in T cell activation explains an observation mentioned in earlier chapters. Protein antigens, such as those used in vaccines, fail to elicit T cell–dependent immune responses unless these antigens are administered with substances that activate APCs, especially dendritic cells. Such substances are called adjuvants, and they function mainly by inducing the expression of costimulators on APCs and by stimulating the APCs to secrete cytokines that activate T cells. Most adjuvants used in experimental immunology are products of microbes (e.g., killed mycobacteria, which is often used in experimental studies) or substances that mimic microbes, and they bind to pattern recognition receptors of the innate immune system, such as Toll-like receptors and NOD-like receptors . Adjuvants used in human vaccines are mainly aluminum salts that induce local inflammation, which secondarily leads to dendritic cell costimulator expression. Thus, adjuvants trick the immune system into responding to purified protein antigens in a vaccine as if these proteins were parts of infectious microbes.

The increasing understanding of costimulators has led to new strategies for inhibiting harmful immune responses. Agents that block B7:CD28 interactions are used in the treatment of disorders in which T cell activation causes organ dysfunction, such as certain autoimmune diseases and graft rejection, and antibodies that block CD40:CD40L interactions are being tested in these diseases.