Balancing functions of regulatory T cells in mosquito-borne viral infections

Abstract

Mosquito-borne viral infections are on the rise worldwide and can lead to severe symptoms such as haemorrhage, encephalitis, arthritis or microcephaly. A protective immune response following mosquito-borne viral infections requires the generation of a controlled and balanced immune response leading to viral clearance without immunopathology. Here, regulatory T cells play a central role in restoring immune homeostasis. In current review, we aim to provide an overview and summary of the phenotypes of FOXP3⁺ Tregs in various mosquito-borne arboviral disease, their association with disease severity and their functional characteristics. Furthermore, we discuss the role of cytokines and Tregs in the immunopathogenesis of mosquito-borne infections. Lastly, we discuss possible novel lines of research which could provide additional insight into the role of Tregs in mosquito-borne viral infections in order to develop novel therapeutic approaches or vaccination strategies.

Keywords: Arboviruses; FOXP3; dengue; immunopathology; regulatory T cells.

Figure 1.

Summary of characteristics and functionalities of Tregs in humans after mosquito-borne viral infections (or vaccination in case of YFV). N/D: not determined, HD: healthy donor. Created with Biorender Text.

Figure 2.

Presence and function of Tregs in the target organs of mosquito-borne viral infections. In DENV, a major target of infection is the liver. In liver biopsies of severe dengue patients, FOXP3⁺ Treg frequencies are reduced while there was an increase in the production of pro-inflammatory cytokines (30). In CHIKV-infected mice, Treg suppressive mechanisms can prevent the accumulation of T cells in the joints leading to less joint inflammation [40,41]. In WNV and JEV-infected mice, Tregs are shown to express CCR5 and CXCR3, indicating that these might migrate to the CNS to restrict immunopathology [67,72]. In cases of fatal microcephaly, the brain is infiltrated with increased frequencies of FOXP3⁺ cells, along with increases in total CD4⁺ and CD8⁺ T cells and increases in Th1, Th2, Th17 and Th9 cytokines [49]. Created with Biorender.

Figure 3.

Summary of the possible beneficial and detrimental roles of Tregs after mosquito-borne viral infections. Tregs could inhibit the formation or activation of virus-specific CD8⁺ T cells resulting in less viral clearance. However, Treg function is needed to dampen excessive immune inflammation by for example M1 macrophages and Treg function is needed in the resolution phase of the infection. Excessive cytokine production as observed in some patients with severe arbovirus infection might impair the generation and function of inducible Tregs. Created with Biorender.