Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/ B7 family

Abstract

Positive and negative costimulation by members of the CD28 family is critical for the development of productive immune responses against foreign pathogens and their proper termination to prevent inflammation-induced tissue damage. In addition, costimulatory signals are critical for the establishment and maintenance of peripheral tolerance. This paradigm has been established in many animal models and has led to the development of immunotherapies targeting costimulation pathways for the treatment of cancer, autoimmune disease, and allograft rejection. During the last decade, the complexity of the biology of costimulatory pathways has greatly increased due to the realization that costimulation does not affect only effector T cells but also influences regulatory T cells and antigen-presenting cells. Thus, costimulation controls T-cell tolerance through both intrinsic and extrinsic pathways. In this review, we discuss the influence of costimulation on intrinsic and extrinsic pathways of peripheral tolerance, with emphasis on members of the CD28 family, CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and programmed death-1 (PD-1), as well as the downstream cytokine interleukin-1 (IL-2).

Fig. 1. Biochemical and transcriptional effects of the CD28 signaling pathways

Summary of biochemical signaling events downstream of the proximal and distal CD28 motifs that can modulate the T-cell transcription pattern after costimulation. Among the different mechanisms, we can distinguish a direct effect on gene expression by regulation of transcription factors or an indirect effect through increases in mRNA stability.

Fig. 2. Preferential localization of liCTLA-4 in lipid rafts

2×10⁸ T cells were activated for 3 days by plate-bound anti-CD3 and anti-CD28 mAbs + IL-2 and lysed. Lysates were subjected to sucrose gradients to separate lipid rafts and membrane fractions. The full length and li forms were immunoprecipitated using anti-CTLA-4 N-terminal (4F10) or anti-CTLA-4 C-terminal (polyclonal) Abs and detected by c-terminal polyclonal Abs by western blot analysis.

Fig. 3. Simplified model of the overall effect of the blockade of individual costimulatory pathways

This simplified model shows the overall result of the blockade of individual costimulation pathways on the balance of effector (Teff) versus regulatory (Tregs) responses. In wildtype (WT) mice, Teff and Treg cells coexist to ensure productive immune responses and their efficient termination; in autoimmune backgrounds, the balance of Teff and Treg cells is skewed towards autoreactivity. In CD28KO mice on a non-autoimmune background, both Teff and Tregs are affected, but CD28 deficiency on Teff still precludes many immune responses. However, on an autoimmune background, Teff cells can bypass the need for CD28 to get fully activated and the defective Treg compartment leads to exacerbated autoimmunity. Deficiency in IL-2 signals affect both Teff and Tregs cells but result in autoreactivity due to improper Teff death and a defective Treg compartment. CTLA-4 deficiency dramatically affects Teff responses and inhibits Treg function (although not their numbers), resulting in dramatic lymphoproliferation and autoimmunity. PD-1 regulates self-antigen-specific T cells, and deficiency in the PD-1/PD-L1 pathway leads to autoimmunity in all backgrounds due to its effect at least on Teff cells and perhaps on Treg cells as well, with particularly dramatic consequences in autoimmune backgrounds.