The plasticity of human Treg and Th17 cells and its role in autoimmunity

Abstract

CD4(+) T helper cells are a central element of the adaptive immune system. They protect the organism against a wide range of pathogens and are able to initiate and control many immune reactions in combination with other cells of the adaptive and the innate immune system. Starting from a naive cell, CD4(+) T cells can differentiate into various effector cell populations with specialized function. This subset specific differentiation depends on numerous signals and the strength of stimulation. However, recent data have shown that differentiated CD4(+) T cell subpopulations display a high grade of plasticity and that their initial differentiation is not an endpoint of T cell development. In particular, FoxP3(+) regulatory T cells (Treg) and Th17 effector T cells demonstrate a high grade of plasticity, which allow a functional adaptation to various physiological situations during an immune response. However, the plasticity of Treg and Th17 cells might also be a critical factor for autoimmune disease. Here we discuss the recent developments in CD4(+) T cell plasticity with a focus on Treg and Th17 cells and its role in human autoimmune disease, in particular multiple sclerosis (MS).

Keywords: Autoimmunity; CD4(+) T cells; FoxP3; IL-17; T cell plasticity; Th17; Treg.

Figure 1. Plasticity of Treg and Th17 cells

Indicated are the major routes of human Treg and Th17 plasticity. Danger signals like extracellular ATP or microbial stimuli can induce cytokine release (e.g. IL-1β) by antigen presenting cells (APC). FoxP3⁺ Tregs can inhibit this process for instance through CD39-mediated hydrolysis of extracellular ATP. Tregs can be induced by IL-12 to become pro-inflammatory IFN-γ producing cells, expressing TBX21 and CXCR3, which loose suppressive capacity while retaining FoxP3 expression (Th1 Treg). In the presence of IL-1β and IL-6 Tregs can acquire a Th17-like phenotype. These cells secrete IL-17 and express RORc, high levels of CCR6 and CD161 but can retain suppressive capacity and FoxP3 expression (Th17 Treg). Highly pathogenic Th17 cells start to express IFN-γ and upregulate TBX21 and CXCR3 in the presence of IL-12 or of IL-1β when primed by C.albicans (indicated by the dotted line) but retain expression of CCR6 and CD161 (Th1 Th17). Th17 cells can also convert into anti-inflammatory IL-4 or IL-10 expressing CD161⁺ CCR6⁺ Th17 cells in the presence of IL-4 or when primed by S.aureus. Additionally, a similar phenotype was observed when Th17 cells were redirected to the small intestine (Th2 Th17).