T cell subsets and their signature cytokines in autoimmune and inflammatory diseases

Abstract

CD4(+) T helper (Th) cells are critical for proper immune cell homeostasis and host defense, but are also major contributors to pathology of autoimmune and inflammatory diseases. Since the discovery of the Th1/Th2 dichotomy, many additional Th subsets were discovered, each with a unique cytokine profile, functional properties, and presumed role in autoimmune tissue pathology. This includes Th1, Th2, Th17, Th22, Th9, and Treg cells which are characterized by specific cytokine profiles. Cytokines produced by these Th subsets play a critical role in immune cell differentiation, effector subset commitment, and in directing the effector response. Cytokines are often categorized into proinflammatory and anti-inflammatory cytokines and linked to Th subsets expressing them. This article reviews the different Th subsets in terms of cytokine profiles, how these cytokines influence and shape the immune response, and their relative roles in promoting pathology in autoimmune and inflammatory diseases. Furthermore, we will discuss whether Th cell pathogenicity can be defined solely based on their cytokine profiles and whether rigid definition of a Th cell subset by its cytokine profile is helpful.

Keywords: Autoimmune disease; Experimental autoimmune encephalomyelitis; Multiple sclerosis; Signature cytokine; T cell subset.

Figure 1. T helper cell subset differentiation and the protective and pathogenic roles of their lineage-signature cytokines

The signature cytokines for each subset are shown in bold. IL-12 induces the expression of T-bet and differentiation into the Th1 subset which produces IFN-γ and TNF; Th2 differentiation and GATA3 expression is induced by IL-4, leading to the production of IL-4, IL-5 and IL-13, whereas TGF-β and IL-4 induce PU.1 expression which causes differentiation into the Th9 subset leading to the production of IL-9. TGF-β induces the expression of Foxp3, which leads to differentiation into the Treg lineage; Th17 differentiation is a result of RORγt expression induced by TGF-β, IL-6 and IL-23, leading to the production of IL-17, IL-22, IL-21, IL-25 and IL-26 (human); IL-6 and TNF induce AHR and differentiation into the Th22 subset and production of IL-22. STAT: Signal transducer and activator of transcription; RORγ: RAR related orphan receptor gamma, AHR: Aryl hydrocarbon receptor, Foxp3: forkhead box P3.

Figure 2. Proposed model of an immune switch point from pathogenic Th17 cells to suppressive exTh17 cells in EAE

TGF-β, IL-6 and IL-23 induce the differentiation of Th17 cells in the immune periphery. In the CNS, signaling by IL-23 induces the expression of GM-CSF and IFN-γ in Th17 cells, thereby rendering these cells pathogenic. In an autocrine signaling loop, IFN-γ suppresses the expression of RORγt and the production of GM-CSF (as well as IL-17) by pathogenic Th17 cells, thereby inducing a switch to “suppressive” exTh17 cells.