The Emerging Roles of Gamma-Delta T Cells in Tissue Inflammation in Experimental Autoimmune Encephalomyelitis

Abstract

γδ (gamma-delta) T cells, a small population of unconventional T cells, have been found in central nervous system lesions of multiple sclerosis (MS) patients, but their function in disease activity is not clearly understood. Previous studies in experimental autoimmune encephalomyelitis (EAE) were inconsistent in identifying their specific roles in suppressing or promoting disease pathogenesis. Emerging advancements in the biology of γδ T cells especially in the context of their being the major initial producers of IL-17, suggested their crucial role in pathogenesis of EAE. In addition, γδ T cells express high levels of IL-23R and IL-1R, which further enhance their effector functions in the pathogenesis of EAE. Nonetheless, activated heterogeneous γδ T cells display functional dichotomy, which is crucial in determining the outcomes of tissue inflammation in EAE. In this review, we discussed recent advances in understanding the biology of γδ T cells in tissue inflammation as well as their roles in suppressing or promoting the development of EAE.

Keywords: Th17 cells; autoimmunity; cytokines; gamma–delta T cells; inflammation.

Figure 1

Peripherally primed γδ T cells execute their effector functions in the CNS in EAE. TLRs and NLRs activated dendritic cells (DCs) and macrophages produce proinflammatory cytokines, such as IL-6, IL-23 and IL-1β. IL-23 and IL-1β are sensed by IL-23R-expressing γδ T cells, which in turn produce early burst of IL-17 during early phase of EAE. On the other hand, IL-6 together with TGF-β induce the differentiation of Th17 cells. γδT17 cells produce IL-21, which further amplify their own generation and also amplify the generation of Th17 cells. Differentiated γδT17 and αβ Th17 cells breach the blood brain barrier to execute their effector functions within the CNS during EAE. Activated microglia/macrophages produce IL-23 within the CNS to promote the generation of γδT17 and Th17 cells. Inflammatory γδT17 cells promote CNS injury in EAE by enhancing the effector functions of Th17 cells and restraining the suppressive functions of Tregs cells.

Figure 2

Dendritic cell-derived IL-23, IL-1β, and IL-18 mediates induction of effector γδT17 cells. Ligation of TLRs on the surface of DCs induces caspase-1 activation in inflammasome-dependent manner. Activated caspase-1 cleaves pro IL-1β and IL-18 into their active forms as shown in the figure. Activated DCs also produce IL-23, which together with IL-1β or IL-18 promote the induction of proinflammatory cytokines, such as IL-17, GM-CSF, IL-21, and IL-22. These effector γδ T cells initiate disease induction and help αβ⁺ CD4⁺ T cells to induce EAE.