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Selective Costimulation Modulators: Addressing Unmet Needs in Rheumatoid Arthritis Management: Costimulatory Activation of T Cells


Costimulatory Activation of T Cells

Regardless of the origin of the stimulating antigen, the T cell requires at least 2 signals for full activation (Figure 3). One signal is delivered by the binding of the antigen/MHC complex on the APC to an antigen-specific receptor on the T-cell surface. The best characterized second, or costimulation, signal is delivered by the interaction between a cell-surface receptor on the T cell (CD28) with its ligands CD80 (B7-1) and CD86 (B7-2) on the APC.[21] When T cells are stimulated by the antigen but do not receive the appropriate costimulation signal, they may enter a quiescent state known as anergy.[22] Anergic cells may fail to proliferate, or they may proliferate but fail to mount an immune response upon subsequent exposure to the antigen. Costimulatory activation initiates the induction of the IL-2 cytokine, stimulates cell proliferation, activates T-cell effector functions, and triggers cell-signaling pathways that promote cell survival.

Figure 3. (click image to zoom) Two signals are required for optimal activation of CD4+ T cells by an antigen-presenting cell (APC). The first signal is generated when the T cell receptor (TCR) binds to its cognate antigen presented in the context of major histocompatibility complex (MHC) class II molecules present on the surface of the APC. Costimulation provided by the binding of the CD28 molecule on the T cell with CD80/86 on the APC generates signal 2.

Multiple costimulation pathways both positively (eg, CD40/CD40L and ICOS/ICOS-L) and negatively (eg, PD-1/PD-1L) regulate T-cell function.[21,23] Among these, the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) cell-surface molecule expressed by activated T cells shares about 30% of the amino acid sequence that makes up CD28 and binds to the same APC ligands, CD80 and CD86, that bind to CD28 (Figure 4).[21,24] CD28 and CTLA4 appear to act as part of a T-cell regulatory system in which activation by CD28 receptors stimulates the production of IL-2 and induces the expression of CTLA4. CTLA4, responding to the same APC ligands, signals a decrease in T-cell activity (Figure 4).[25] The central role of CTLA4 in immune regulation is illustrated by findings from in vitro model systems, in which signaling through CTLA4 suppresses T-cell proliferation and cytokine production, and from animal studies, in which mice lacking this receptor develop aggressive lymphoproliferative disorders and premature mortality.[26-28] CTLA4 is expressed by T cells within 24 hours after activation, reaching a peak after approximately 48-96 hours and then decreasing.[25] In vitro studies have found that CTLA4 binds to CD80 and CD86 with much greater affinity than does CD28 by a factor of approximately 2500 for CD80 and approximately 570 for CD86.[29] Thus, the negative effects of CTLA4 on T cells may occur as a result of 2 independent variables; engagement of CD80/86 by CTLA4 directly activates negative signaling pathways within the T cell, but also blocks the positive signaling pathways induced when CD28 binds to CD80/86, as CTLA4 would naturally outcompete CD28 for these ligands.[30,31] Both of these mechanisms that are used by CTLA4 to control T-cell activation could form the basis of potential new therapeutics for RA. Because physiological emulation of intracellular signaling pathways is an often difficult and impractical endeavor, modulation of T-cell activation through a blockade of CD28 costimulation may be the most attractive approach.

Figure 4. (click image to zoom) Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) outcompetes CD28 for binding of CD80/86 on the APC and provides a negative feedback control, thus attenuating activated T cells.