Targeting co-stimulatory pathways: transplantation and autoimmunity

Abstract

The myriad of co-stimulatory signals expressed, or induced, upon T-cell activation suggests that these signalling pathways shape the character and magnitude of the resulting autoreactive or alloreactive T-cell responses during autoimmunity or transplantation, respectively. Reducing pathological T-cell responses by targeting T-cell co-stimulatory pathways has met with therapeutic success in many instances, but challenges remain. In this Review, we discuss the T-cell co-stimulatory molecules that are known to have critical roles during T-cell activation, expansion, and differentiation. We also outline the functional importance of T-cell co-stimulatory molecules in transplantation, tolerance and autoimmunity, and we describe how therapeutic blockade of these pathways might be harnessed to manipulate the immune response to prevent or attenuate pathological immune responses. Ultimately, understanding the interplay between individual co-stimulatory and co-inhibitory pathways engaged during T-cell activation and differentiation will lead to rational and targeted therapeutic interventions to manipulate T-cell responses and improve clinical outcomes.

Figure 1. Complexities of the CD28 co-stimulatory pathway

The CD28 co-stimulatory receptor can be ligated by CD80, CD86, and ICOS-L (B7-H2). The CTLA-4 co-inhibitor competes with CD28 for binding to CD80 and CD86. However, CD80 can also bind to PD-L1 (B7-H1) and deliver a co-inhibitory signal. ICOS competes with CD28 for binding to B7-H2. Abbreviations: B7-H1, programmed cell death 1 ligand 1; B7-H2, ICOS ligand; CD28, T-cell-specific surface glycoprotein CD28; CD80, T-lymphocyte activation antigen CD80; CD86, T-lymphocyte activation antigen CD86; CTLA-4, cytotoxic T-lymphocyte protein 4; ICOS, inducible T-cell costimulator; PD-L1, programmed cell death 1 ligand 1;

Figure 2. Comparison of abatacept and belatacept with selective CD28 blockade, and implications for T-cell activation

Abatacept and belatacept are both CTLA-4-Ig fusion proteins that bind to both CD80 and CD86 on the surface of APCs, thereby blocking both CD28 co-stimulatory signals as well as CTLA-4 co-inhibitory signals. By contrast, anti-CD28 (dAb) and scFVs each bind selectively to co-stimulatory CD28, inhibiting its binding to CD80 and CD86 while leaving intact the binding of the CTLA-4 co-inhibitor with these ligands. Abbreviations: APCs, antigen presenting cells; CD28, T-cell-specific surface glycoprotein CD28; CD80, T-lymphocyte activation antigen CD80; CD86, T-lymphocyte activation antigen CD86; CTLA-4, cytotoxic T-lymphocyte protein 4; dAb, domain antibody; Ig, immunoglobulin; scFV, single-chain variable fragment.

Figure 3. Co-stimulatory pathways that might modulate memory T-cell responses in transplantation and autoimmunity

Some co-stimulatory pathways have been shown to be particularly important for memory T-cell responses in transplantation and autoimmunity. Abatacept and belatacept (both CTLA-4-Ig fusion proteins) and anti-CD28 domain antibodies might target memory T-cell responses by disrupting the CD28 and CTLA-4 pathway. Monoclonal antibodies against ICOS, OX40L (oxelumab), and LFA-1 (efalizumab) target ICOS and ICOS-L, OX40L and OX40, and LFA-1 and ICAM interactions, respectively. Alefacept is LFA-3 Ig fusion protein that competitively inhibits CD2 ligation of LFA-3 on APCs. Abbreviations: APC, antigen presenting cell; CD2, T-cell surface antigen CD2; CD28, T-cell-specific surface glycoprotein CD28; ICAM, Intercellular adhesion molecule 3; CD80, T-lymphocyte activation antigen CD80; CD86, T-lymphocyte activation antigen CD86; ICOS, Inducible T-cell costimulator; CTLA-4, Cytotoxic T-lymphocyte protein 4;LFA-1, Integrin αL (CD11a)/ integrin beta2 (CD18); Ig, immunoglobulin; LFA-3, Lymphocyte function-associated antigen 3; OX40, tumour necrosis factor receptor superfamily member 4; OX40L, tumour necrosis factor ligand superfamily member 4; B7h1, programmed cell death 1 ligand 1; pMHC, peptide/ major histocompatibility complex; TCRα, T-cell receptor alpha chain