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

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.

Keywords: dendritic cell, polarization, T-cell, Th1, Th2, Th17
INTRODUCTION: T-HELPER CELL SUBSETS
Naive T helper (Th) cells are activated by recognition of a peptide antigen–class II major histocompatibility complex (MHC) presented on antigen-presenting cells (APCs) through the interaction with the T-cell receptor (TCR). After activation, Th cells begin to divide and/or give rise to a clone of effector cells, each specific for the same antigen–class II MHC complex.1 These effector Th cells are CD4+ and can be divided into three main types, with distinct cytokine-secretion phenotypes eliciting unique functional characteristics for each type. These cells are referred to as Th type-1 (Th1), Th type-2 (Th2) or Th type-17 (Th17) cells, depending on their phenotype. Th1 cells secrete the cytokines interferon (IFN)-γ, and tumour necrosis factor (TNF)-β, which allow these cells to be particularly effective in protecting against intracellular infections by viruses and bacteria and micro-organisms that grow in macrophages, as well as eliminating cancerous cells.2,3 Th2 cells secrete interleukin (IL-4), -5, -10 and -13, which up-regulate antibody production and target parasitic organisms. Th2 cells activate B cells, which are adapted for defence against parasites that are vulnerable to IL-4-switched immunoglobulin (Ig)E production, IL-5-induced eosinophilia, and IL-3- and IL-4-stimulated mast cell proliferation and degranulation. Th2 cells are predominately responsible for the development of asthma. Until recently the latter two subsets were considered to be the only types of CD4 effector responses; however, studies over the last few years have revolutionized this area of immunology with the discovery of a third subset known as Th17 cells.