Heterogeneity of human effector CD4+ T cells

Abstract

For many years the heterogeneity of CD4+ T-helper (Th) cells has been limited to Th1 and Th2 cells, which have been considered not only to be responsible for different types of protective responses, but also for the pathogenesis of many disorders. Th1 cells are indeed protective against intracellular microbes and they are thought to play a pathogenic role in organ-specific autoimmune and other chronic inflammatory disorders. Th2 cells provide protection against helminths, but are also responsible for the pathogenesis of allergic diseases. The identification and cloning of new cytokines has allowed one to enlarge the series of functional subsets of CD4+ Th effector cells. In particular, CD4+ Th cells producing IL-17 and IL-22, named Th17, have been initially implicated in the pathogenesis of many chronic inflammatory disorders instead of Th1 cells. However, the more recent studies in both humans and mice suggest that Th17 cells exhibit a high plasticity toward Th1 cells and that both Th17 and Th1 cells may be pathogenic. More recently, another two subsets of effector CD4+ Th cells, named Th9 and Th22 cells, have been described, even if their pathophysiological meaning is still unclear. Despite the heterogeneity of CD4+ effector Th cells being higher than previously thought and some of their subsets exhibiting high plasticity, the Th1/Th2 paradigm still maintains a strong validity.

Figure 1

Main populations of CD4⁺ effector T cells. When the naïve CD4⁺ T-helper (Th) cell recognizes a given antigen on the surface of the antigen-presenting cell (APC), the cytokines present in the microenvironment created by the response of the innate immunity play a critical role in dictating the type of effector cell that is subsequently induced. In the presence of IL-2 and IL-4, the naïve Th cell expresses the transcription factor GATA-binding protein-3 (GATA-3) and differentiates into a Th2 cell that, because of its ability to produce IL-4, IL-5, IL-9 and IL-13, is protective against extracellular parasites, but can also be responsible for allergic disorders. In the presence of IL-4 and transforming growth factor beta (TGFβ), the Th2 cell can further differentiate into a Th9 cell, which produces IL-9 and IL-10, whose pathophysiological meaning as well as the possibility that they can also directly originate from the naïve Th cell are still unclear. In the presence of interferons (IFNs) and IL-12, the naïve Th cell expresses T-box expressed in T cells (T-bet) and differentiates into a Th1 cell that, because of the production of IFNγ and lymphotoxin-α (LTα), induces delayed type hypersensitivity (DTH) reactions that are protective against intracellular bacteria, fungi and protozoa, but can also be responsible for autoimmune disorders such as experimental autoimmune encephalomyelitis (EAE), experimental autoimmune uveitis (EAU), and peptoglycan-induced arthritis (PIA). In the presence of TNF and IL-6, the naïve Th cells express aryl hydrocarbon receptor (AHR) and differentiate into a Th22 cell that, because of its production of IL-22 and the expression of skin homing chemokine receptors (CCR4 and CCR10), has been hypothesized to be important in skin homeostasis and pathology. In the presence of TGFβ, IL-6 and IL-21 (in mice) or of IL-1 and IL-23 (in humans), the naïve Th cell expresses retinoic acid-related orphan receptor (ROR)γt and differentiates into a Th17 cell that, because of its production of IL-17A, IL-17F, IL-21 and IL-22, is involved in the protection against extracellular bacteria and fungi, but can also be responsible for autoimmune disorders, such as EAE, EAU and collagen-induced arthritis (CIA). The possibility that the Th17 cell is flexible and can shift in the presence of IL-12 to Th1 has been observed in both humans and mice. NK, natural killer cell.