Immunological decision-making: how does the immune system decide to mount a helper T-cell response?

Abstract

Aberrant T-cell responses underpin a range of diseases, including asthma and allergy and autoimmune diseases. Pivotal immune elements of these diseases are the development of antigen-specific effector T-helper type 2 (Th2) cells, Th1 cells, or the recently defined Th17 cells that are associated with the clinical features and disease progression. In order to identify crucial processes in the pathogenesis of these diseases it is critical to understand how the development of these T cells occurs. The phenotype of a polarized T-cell that differentiates from a naïve precursor is determined by the complex interaction of antigen-presenting cells with naïve T cells and involves a multitude of factors, including the dominant cytokine environment, costimulatory molecules, type and load of antigen presented and a plethora of signaling cascades. The decision to take the immune response in a certain direction is not made by one signal alone, instead many different elements act synergistically, antagonistically and through positive feedback loops to activate a Th1, Th2, or Th17 immune response. The elucidation of the mechanisms of selection of T-cell phenotype will facilitate the development of therapeutic strategies to intervene in the development of deleterious T-cell responses. This review will focus on the pathways and key factors responsible for the differentiation of the various subsets of effector CD4 T cells. We will primarily discuss what is known of the Th1 and Th2 differentiation pathways, while also reviewing the emerging research on Th17 differentiation.

Figure 1

Initiation of the immune response and determination of phenotype. Pathogen-associated molecular patterns (PAMPs) are recognized by antigen-presenting cells (APCs), which present antigenic components bound to major histocompatibility complex II (MHC II) and a variety of costimulatory molecules and cytokines are released, which are determined by the nature of the pathogen. Tissue factors are released by infected tissues and influence APC activity. The nature of cytokines and costimulatory factors determines the phenotype of T-cell development and the effects of these signals are reinforced by cytokine release from the T cells themselves. T cells develop in stages, which are controlled by the interaction of a variety of controlling mechanisms. Negative-feedback loops ensure the predominance of a single phenotype, and tolerant mechanisms exist to prevent excessive responses to innocuous or self-antigens. Polarizing factors: T helper type-1 (Th1); interleukin (IL)-12, interferon (IFN)-α, -β, or -γ, IL-18, IL-27, CD80, intercellular adhesion molecule 1 (ICAM1), T helper type-2 (Th2); IL-4, IL-6, IL-11, CD2 and CD86. Tissue factors: cytokines; chemokines; eicosenoids; heat shock proteins; necrotic cell lipids. Phenotype determinants: nature and load of antigen; T-cell receptor (TCR); coreceptor signals; cytokine environment. Stages of development: 1, activation of cytokine genes; 2, Th cell commitment to phenotype; 3, repression of opposing Th cells; and 4, stabilization of phenotype. The molecular mechanisms that control the stages of development include intracellular signaling cascades, chromatin remodeling and epigenetic factors. CTLA-4, cytotoxic T lymphocyte antigen-4; ICOS, inducible costimulator; ICOS-L, inducible costimulator ligand; PRR, pattern recognition receptor; TGF-β, transforming growth factor-β; TLR, Toll-like receptor; TNF-β, tumour necrosis factor-β; Treg, regulatory T-cell.

Figure 2

Role of dendritic cells (DCs) in the development of the T-cell phenotype. DCs develop from progenitor cells in the bone marrow. DCs enter the circulation as immature cells and traffic to peripheral tissues and areas of potential pathogen exposure, where they perform continual surveillance for pathogens. Immature DCs are activated by pathogen-associated molecular patterns (PAMPs) and tissue factors, which induce the maturation of DCs into specific subsets characterized by the types of cytokines and costimulatory factors that they express. Mature DCs then move into lymphoid tissues where they induce the development of different phenotypes of T cells, depending on the nature of the DC. Th1, T helper type-1; Th2, T helper type-2; Treg, regulatory T-cell.

Figure 3

T-cell polarizing factors. T-cell receptors (TCRs) on the naïve T-cell (Th0) bind to antigen presented by antigen-presenting cells (APCs), which leads to the tyrosine phosphorylation of immuno-receptor tyrosine-based activation motifs (ITAMs). This induces the release of adaptor molecules [e.g. linker for activated T cells (LAT), protein kinase C], which results in the sequential activation of GTPases, mitogen-activated protein kinases (MAPKs) and activator protein-1 (AP-1), which induces T-cell proliferation (a) Upon T-cell activation, phospholipase C (PLC) activity is induced, which breaks down membrane-associated phosphatidylinositol-bis-phosphate (PIP₂) into the intracellular second messengers inositol-1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ induces calcium release, which results in cytokine expression, and DAG stimulates protein kinase C and causes T-cell activation through the MAPK pathway. The type of cytokine expressed is the most important factor influencing the phenotype of the developing T cells. Cytokines bind to their receptors on Th0 cells and activate Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathways. Different combinations of JAK and STAT molecules are generated in response to different cytokines and induce different signaling cascades, which drive the development of the specific T-cell phenotype. Interferon-γ (IFN-γ) and interleukin (IL)-12 induce JAK1/2 and STAT1/3/4 to stimulate T-bet and further IFN-γ production, resulting in a T helper type-1 (Th1) response, whereas IL-4 triggers JAK1/3 and STAT6 to activate GATA-3 and a T helper type-2 (Th2) response. Features of Th1 cells: Th1 cytokines; increased Ca²⁺, IFN-γ and IL-12; decreased protein kinase C and GATA-3 (IFN-γ and IL-12 mediated). Features of Th2 cells: Th2 cytokines; increased monocytic chemotactic protein-1 (MCP-1) and protein kinase C; decreased Ca²⁺. CTLA-4, cytotoxic T lymphocyte antigen-4; NFAT, nuclear factor of activated T cells.

Figure 4

The development and function of T helper type-17 (Th17) cells. Interleukin (IL)-6 acts to induce IL-21 secretion from T cells, which then acts in concert with transforming growth factor-β (TGF-β) to induce the development of Th17 cells from naive T cells. Th17 cells are activated by binding of IL-23 to the IL-23 receptor (IL-23R), which is up-regulated by TGF-β and IL-21 stimulation. TGF-β and IL-21 activate signal transducer and activator of transcription 3 (STAT3), which induces the transcription factor retinoic acid receptor-related orphan receptor γ-t (RORγt), responsible for Th17 differentiation. Th17 activation induces the release of IL-17, IL-17F, IL-6, IL-22 and tumour necrosis factor-α (TNF-α), which activate a variety of innate immune and structural cells. These cells release inflammatory mediators and chemokines that recruit neutrophils and induce generalized tissue inflammation in order to destroy extracellular bacteria but are also involved in autoimmune diseases.