Introduction to Costimulation and Costimulatory Molecules

The immune system has the remarkable ability to defend against a diversity of microbial pathogens, yet not respond to self. Activation of this immune system is dependent on both innate and adaptive responses to environmental challenges such as infection. Activation of adaptive immune responses requires signals through antigen-specific T- and B-cell receptors. However, this antigen-specific signal alone is not sufficient to drive the activation of naive T cells and requires a second antigen-independent nonspecific signal known as costimulatory signal. The primary source of this costimulatory signal is interactions between the T-cell integral membrane proteins and their corresponding ligands on the APC. Currently, the B7 family has seven members (B7-1, B7-2, ICOS-L, PD-L1, PD-L2, B7-H3, and B7-H4), and the TNFR family has six members (HVEM, BTLA, CD70, CD30, 4-1BBL is also known as CD137 is a type II glycoprotein belonging to the tumor necrosis factor superfamily (4-IBB-L), and OX40L). The best-defined costimulatory pathway, to date is the B7-1/B7-2/CD28 pathway, and this has been shown to constitute the primary and strongest costimulatory signal delivered by APCs to amplify T-cell activation. The biologic consequences of CD28 costimulation include increased cytokine gene expression, stabilization of cytokine messenger RNA, augmentation of glucose uptake and utilization, promotion of T-cell survival, and maintenance of T-cell responsiveness upon subsequent restimulation. With the rapid increase in knowledge of the function of a growing number of specific costimulatory molecules, costimulation is now starting to be recognized as the master switch for T-cell activation and modulation of T-cell function. Therefore, understanding the relationships between the costimulatory ligands and their receptors in different immune effector pathways will surely help us in improving immunomodulatory therapeutics, development of improved vaccines, and avoidance of unintended tissue injury.

Keywords

Costimulation; antigen-presenting cells; ligands; receptors; naive T cells; major histocompatibility complex; pathogens

Introduction

We live in an environment that contains a huge range of pathogenic microbes and toxic substances that threaten normal homeostasis and challenge the host by a very broad selection of pathogenic mechanisms. Pathogenic microbes possess a diverse collection of mechanisms by which they replicate, spread, and threaten normal host functions. The immune system must eliminate pathological microbes and toxic or allergenic proteins, and at the same time, it must avoid responses that produce excessive damage of self-tissues or that might eliminate beneficial, commensal microbes. It is not surprising, therefore, that the immune system uses a complex array of protective mechanisms to control and usually eliminate these organisms and toxins. A general feature of the immune system is that these mechanisms rely on detecting structural features of the pathogen or toxin that mark it as distinct from host cells. Such host–pathogen or host–toxin discrimination is essential to permit the host to eliminate the threat without damaging its own tissues.

Our immune system uses many mechanisms to combat infection by microbes. These mechanisms work together, and the fully integrated immune response draws elements from many effector systems in order to tailor a response to the specific invading pathogen. Activation of the immune system is dependent upon both innate and adaptive responses to environmental challenges such as infection. Activation of adaptive immune responses requires signals through antigen-specific T- and B-cell receptors (TCRs and BCRs, respectively). But this antigen-specific signal alone was not sufficient to drive the activation of naive T cells and led to the concept of two-signal model of T-cell activation, according to which productive T-cell activation requires a first signal provided by the interaction of antigenic peptide/major histocompatibility complex (MHC) with the TCR and a second, antigen-independent cosignal, the “costimulatory signal.” The “first signal” delivered by the TCR mediates the specificity of a T-cell response via the recognition of specific epitopes of a given antigen presented in combination with the MHC on antigen-presenting cells (APCs). However, activation of T cells by this receptor interaction alone fails to induce cytokine production and sustained proliferation, but rather results in T-cell apoptosis, or the induction of specific nonresponsiveness (anergy) to subsequent stimulation with the same antigen.1 This gives rise to the concept of the two-signal model of T-cell activation (Figure 1.1). According to the two-signal model, T cells, to become fully activated, require additional signals delivered by the so-called costimulatory molecules. These molecules are transmembrane proteins that induce an intracellular signaling cascade via their cytoplasmic tail that modifies the TCR-mediated signal. Costimulatory molecules cannot activate T cells without concomitant TCR cross-linking. According to this definition, adhesion molecules such as intercellular adhesion molecule-1 are not costimulatory because they enhance T-cell activation merely by facilitating the contact between T cell and APC. Furthermore, T-cell costimulation refers to a signal that is delivered to the T cell exclusively. In this respect, the CD40–CD40L interaction is also not considered as costimulatory, although this is an important receptor–ligand pair in T/B cooperation. The dependence of T-cell activation on this “second signal” delivered by costimulators adds a second line of regulation to antigen-specific T-cell responses that reaches far beyond a mere “on–off” command. With a growing number of both stimulatory and inhibitory costimulatory molecules being identified, the classic concept of costimulation as a two-signal event has changed. T cells simultaneously express an adjustable spectrum of costimulatory molecules. Today, T-cell costimulation is recognized as an integrating process of various positive and negative signals that determine the mode of T-cell activation.2 The T-cell response to any given antigen involves the clonal expansion of a small number of T cells that share specificity but express unique TCRs. The integration of signals generated by these interactions determines the final outcome of encounters between T cells and APCs. The primary source of this costimulatory signal is interactions between the T-cell integral membrane protein CD28 and its ligands, B7-1 and B7-2, on the APC. Currently, the B7 family has seven members (B7-1, B7-2, inducible costimulator ligand (ICOS-L), programmed death ligand-1 (PD-L1), PD-L2, B7-H3, and B7-H4), whereas tumor necrosis factor (TNF) receptor (TNFR)/TNF family has six members (herpes virus entry mediator (HVEM), B- and T-lymphocyte attenuator (BTLA), CD70, CD30, 4-IBB-L, and OX40L) (Table 1.1 and Figure 1.2). The B7 family includes transmembrane or glycosylphosphatidylinositol-linked proteins characterized by extracellular IgV and IgC domains. B7-1 and B7-2 can engage either CD28 or cytotoxic T-lymphocyte antigen-4 (CTLA-4), resulting in complex positive and negative regulation of antigen receptor signaling.3 ICOS-L is the only identified ligand for inducible costimulator (ICOS). Both PD-L1 and PD-L2 engage programmed death-1 (PD-1), although data suggest the existence of additional receptors for PD-L1 and PD-L2. Receptors for B7-H3 and B7-H4 have not been identified, although expression of these ligands modulates immune responses. The cell surface expression of B7 ligands is highly regulated, although, in general, ligands for costimulatory receptors are constitutively expressed on APCs, whereas ligands for coinhibitory receptors are expressed after induction by various inflammatory stimuli. The activation of a T cell is thus dictated by the integration of signals derived from the TCR, CD28, and CTLA-4. By regulating the expansion of individual T cells, CD28 and CTLA-4 could modulate the composition of a polyclonal antigen-specific T-cell response. The balance between activating signals generated by CD28 and inhibitory signals delivered by CTLA-4 determine the outcome of a T cell’s interaction with an APC.