T and B Cell Activation and Costimulation

It is generally accepted that T cells require two signals in order to undergo activation and clonal expansion. The first of these activating signals, "signal-1" is initiated when the T cell receptor (TCR) is crosslinked following engagement with MHC bound peptides expressed on antigen presenting cells (APC). The second signal, "signal-2," is provided when one of several receptor proteins expressed on a T cell is crosslinked by its ligand expressed on the APC. Collectively, these T cell surface receptors are referred to as T cell costimulatory receptors, of which CD28 and the CD28-CTLA-4-CD80/CD86 signaling pathway is the prototype. CD28 and CTLA-4 are members of the immunoglobulin (Ig)-superfamily (Brunet et al., 1987; Linsley et al., 1991; Salomon and Bluestone, 2001), and both share the same ligands CD80 (B7.1) or CD86 (B7.2). CD28 is constitutively expressed

ANERGY/APOPTOSIS

ACTIVATION/CLONAL EXPANSION

(Signal 1 only)

CD4+ T CELL

CD4+ T CELL

Figure 5.1. T cells require two signals for activation. T cell activation is initiated when the TCR binds a complex composed of pathogen-derived peptides and MHC molecules displayed on the surface of an APC (Signal-1). In the absence of additional signals the T cell becomes anergic (Gimmi et al., 1993) or dies by apoptosis (Wolf et al., 1994). Cognate recognition of the APC by the T cell allows CD28 to bind its ligand on the APC thus initiating Signal-2. The combination of both signals drives T cell clonal expansion, differentiation and memory.

Figure 5.1. T cells require two signals for activation. T cell activation is initiated when the TCR binds a complex composed of pathogen-derived peptides and MHC molecules displayed on the surface of an APC (Signal-1). In the absence of additional signals the T cell becomes anergic (Gimmi et al., 1993) or dies by apoptosis (Wolf et al., 1994). Cognate recognition of the APC by the T cell allows CD28 to bind its ligand on the APC thus initiating Signal-2. The combination of both signals drives T cell clonal expansion, differentiation and memory.

on T cells where it functions as a T cell costimulatory molecule. CTLA-4 is an activation inducible receptor that functions as a negative regulator of T cell activation (Waterhouse et al., 1995). The ligands for these receptors are differentially expressed on APC. For instance, CD80 is not expressed on resting APC, while CD86 can, but only at low levels. CD80 and CD86 upregulation is secondary to TCR binding to peptide MHC complexes, and their appearance is dependent upon rapidly induced expression of CD40 ligand (CD154) on the T cell. CD154 is an activation inducible type II transmembrane protein that binds CD40 a costimula-tory receptor constitutively expressed at varying levels on APCs and B cells. The CD154-CD40 signaling pathway induces APC activation that drives the subsequent expression, or upregulation of CD80 and CD86 on the APC, and this in turn facilitates CD28 receptor crosslinking (Figure 5.1).

Since the recognition of CD28 as a T cell costimulatory receptor other costimulatory receptors belonging to the Ig, CD2, and TNFR superfamilies have been identified. Within the TNFR superfamily CD27, CD30, CD134 (OX40), CD137 (4-1BB), herpes virus entry mediator (HVEM), and glucocorticoid-induced tumor necrosis factor receptor family related gene (GITR) have all been shown to serve as costimulatory receptors for T cells (Watts, 2005).

CD28 engagement with its CD80/CD86 ligands, lowers the activation threshold needed for antigen receptor-induced activation (Viola and Lanzavecchia, 1996), increases the half-life of IL-2 mRNA in the T cell (Chen et al., 1998; Linsley et al., 1991), upregulates transcription of anti-apoptotic genes (Boise et al., 1995a), and protects the T cell from activation induced cell death (AICD) (Boise et al., 1995a, 1995b; Gribben et al, 1995; Mueller et al, 1996; Noel et al, 1996; Radvanyi et al., 1996; Van Parijs et al., 1996; Walunas et al., 1996). Once activated through

T Cell Cytokines

CD4 T Cell

Signal 1

CD4 T Cell

Ag-induced BCR Aggregation

Signal 2

^ dt ill .Antigen

Ag-induced BCR Aggregation

^ dt ill .Antigen

Signal 2

Ig Isotype switch B Cell Anti-apoptotic genes

Figure 5.2. CD4 T cell-mediated Ig class switching. CD4 T cells provide help to B cells that drives them into the cell cycle, protects them from apoptosis, and allows the B cell to class switch the antibody it produces from IgM to IgG, IgA, or IgE (Snapper and Mond, 1993). This process of help occurs in germinal centers and requires cognate recognition of CD40 with its ligand CD154 and usage of T cell derived cytokines such as IL-4, IL-5, TGF-|3, and IFN-y by the B cell.

antigen-dependent and costimulatory signals, CD4 T and CD8 T cells undergo clonal expansion and differentiate into effector helper and cytolytic T cells, respectively. Activated CD4 T effector cells produce either pro-inflammatory cytokines (Th1), or anti-inflammatory cytokines (Th2).

CD4 T cells also provide help to antigen-activated B cells through cytokine and CD154-CD40 dependent pathways (Durie et al, 1994). CD154-mediated CD40 crosslinking on B cells induces transcription of anti-apoptotic genes and drives immunoglobulin class switching. CD4 T cells, in addition to crosslinking CD40, produce cytokines needed to promote B cell differentiation. Cytokines also help determine which class of antibody the B cell will produce, i.e., they help drive class switch recombination events that permit B cells to switch from IgM production to producing IgG, IgA, or IgE class antibodies (Foy et al., 1993; Kawabe etal., 1994; Kelsoe, 1996;Renshaw etal, 1994; van Essen etal, 1995; Xu etal, 1994). Thus, like T cells, B cells require two distinct signals for their full activation and survival. The first is generated through antigen-induced BCR crosslinking and the second, through CD154-induced crosslinking of CD40 (Figure 5.2). In humans, mutations in the CD154 protein leads to a heritable disease called hyper-IgM syndrome. Individuals afflicted with this disease can have elevated levels of IgM in their serum but have low to non-detectable levels of IgG, IgA, or IgE (Allen et al., 1993; Aruffo etal, 1993; DiSanto etal, 1993; Korthauer etal, 1993).

Following infection, B cells respond by producing IgM class antibodies. The majority of B cells producing these antibodies respond to bacterial wall polysaccharides and lipopolysaccharides whose structure is highly repetitive. Antigens of this type elicit antibody responses independent of T cell help because their repetitive antigenic determinants extensively crosslink the BCR; antigens of this type are said to be T-independent (TI) antigens (Snapper and Mond, 1996). As the infection proceeds and the immune system expands its response, the breadth of the B cell response broadens and the majority of antigens that B cells encounter lack highly repetitive subunit structures. These antigens do not crosslink BCR sufficiently to drive B cell expansion and differentiation. In order for B cells to respond to these antigens they require T cell help, thus antigens of this type are classified as T-dependent antigens (TD). The distinction between T-independent and T-dependent antigens is important in the context of this review because interference with T cell costimulation blocks the induction of T-dependent humoral immunity but not T-independent humoral immune responses.

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