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

Abstract

Summary 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).

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

“…Multiple T cell co-stimulatory and co-inhibitory receptors act in concert to regulate the activation, proliferation and effector functions of T lymphocytes. CD28 and CTLA-4 are among the best characterized T cell co-stimulatory and co-inhibitory molecules, respectively [3]. Both molecules are expressed on the surface of selected T populations and transmit opposing signals upon interaction with their ligands, CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells [3].…”

FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression

“…This requirement of CD28 in the periphery varies based on anatomical location, stage of immune response, nature of T-cell subsets, and the activation status of the CD4 ϩ T-cells (7)(8)(9). CD28 co-signal is a quantitative signal that overcomes the signal threshold necessary for T-cell activation, otherwise unattainable by the TCR ligation alone (10). In an autoimmune background, T-cell activation occurs without the requirement of CD28 co-signal (10).…”

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

“…As a consequence, deficiency in CTLA-4 function results in severe antigen-nonspecific autoimmune phenotypes. 10 In contrast, the effect of engaging PD-1 is mainly cell intrinsic. The cellintrinsic function of PD-1, as well as the regulation of PD-1 expression, might be responsible for the chronic and relatively milder pathologic phenotypes resulting from PD-1 blockade through either antibody-masking or genetic manipulation.…”