APC-derived cytokines and T cell polarization in autoimmune inflammation

Abstract

T cell-mediated autoimmune diseases such as multiple sclerosis and rheumatoid arthritis are driven by autoaggressive Th cells. The pathogenicity of such Th cells has, in the past, been considered to be dictated by their cytokine polarization profile. The polarization of such effector T cells relies critically upon the actions of cytokines secreted by APCs. While Th1 polarization has long been associated with the pathogenesis of autoimmune diseases, recent data obtained in gene-targeted mice and the discovery of Th17 cell involvement in autoimmunity conflict with this hypothesis. In light of these recent developments, we discuss in this review the actions of APC-derived cytokines and their emerging roles in T cell polarization in the context of autoimmune inflammatory responses.

Figure 1. Within the immune synapse formed between APCs and T cells, three signals are required for antigen-specific T cell activation.

Signal 1 comprises the presentation of antigen peptide, in the context of MHC class II molecules, which is recognized by the antigen-specific TCR. Signal 2 involves the stabilization of the synapse through adhesion molecules and the generation of signals via costimulatory molecules present on the surface of APCs and T cells. CD80/CD86 on APCs interact with their receptor, CD28, on T cells to generate activatory signals, while interaction with cytotoxic T lymphocyte–associated protein 4 (CTLA4) generates inhibitory signals (not shown). Signal 3 is produced by the secretion of cytokines by APCs, which signal via cytokine receptors on T cells in order to polarize them toward an effector phenotype. Ag, antigen.

Figure 2. APC-derived cytokines guide the differentiation of naive T cells into an effector T cell subtype.

Secretion of IL-12, in synergy with IL-18, leads to the generation of Th1 cells. Initial IL-12 production directs the upregulation of IL-18R and IL-12Rβ2 expression on the surface of Th1 precursor (Th1p) cells that allows IL-18 to aid IL-12 in Th1 polarization. TGF-β secretion can polarize naive cells toward a regulatory phenotype or an autoaggressive phenotype, depending on the cytokine environment: secretion of TGF-β alone by APCs supports Treg formation (which counteracts autoimmune inflammation) from Treg precursor cells (Treg-p cells). However, the additional presence of IL-6 results in the production of Th17 cells, which are now considered to be the pathogenic T cell population during autoimmunity. The pathogenic, APC-derived cytokine IL-23 is critical for the maintenance and survival of these autoreactive Th17 cells. The interaction of APCs and Th2 precursor (Th2p) cells in the absence of IL-12 and IL-18 induces the production of the Th2 cytokine IL-4 by T cells, which acts in an autocrine fashion to polarize committed Th2 cells.