Toxoplasma gondii: CD8 T Cells Cry for CD4 Help.

Imtiaz A Khan,Magali Moretto,Sujin Hwang

doi:10.3389/fcimb.2019.00136

Imtiaz A Khan, Magali Moretto + Show 1 more

Open Access

https://doi.org/10.3389/fcimb.2019.00136

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Abstract

Toxoplasma gondii, an apicomplexan parasite, is a pathogenic protozoan that can infect the central nervous system. In pregnant women, infection can result in congenital problems of the fetus, while in immunocompromised individual it can lead to severe neurological consequences. Although CD8 T cells play an important effector role in controlling the chronic infection, their maintenance is dependent on the critical help provided by CD4 T cells. In a recent study, we demonstrated that reactivation of the infection in chronically infected host is a consequence of CD8 T dysfunction caused by CD4 T cell exhaustion. Furthermore, treatment of chronically infected host with antigen-specific non-exhausted CD4 T cells can restore CD8 T cell functionality and prevent reactivation of the latent infection. The exhaustion status of CD4 T cells is mediated by the increased expression of the transcription factor BLIMP-1, and deletion of this molecule led to the restoration of CD4 T cell function, reversal of CD8 exhaustion and prevention of reactivation of the latent infection. In a recent study from our laboratory, we also observed an increased expression of miR146a levels by CD4 T cells from the chronically infected animals. Recent reports have demonstrated that microRNAs (especially miR146a) has a strong impact on the immune system of T. gondii infected host. Whether these molecules have any role in the BLIMP-1 up-regulation and dysfunctionality of these cells needs to be investigated.

Highlights

Toxoplasma gondii, an Apicomplexan with broad geographical representation, can cause severe infection of the central nervous system (Torgerson et al, 2014)
Studies conducted in an TE model have demonstrated that during the later stages of the chronic infection, CD8 T cells exhibit a graded increase in the expression of inhibitory receptor PD-1 resulting in their dysfunctionality/exhaustion (Bhadra et al, 2011a)
Treatment of infected animals with a 4-1BB agonist increased the ability of these animals to control parasite multiplication and increased the ability of infected animals to release IL21 (Khan et al, 2019), a cytokine produced predominantly by CD4 T cells (Suto et al, 2008) and known to be important for the maintenance of CD8 T cell functionality (Shin et al, 2009). These findings suggest the importance of co-stimulatory molecules in the maintenance of CD4 T cell functionality during a chronic infection, which can be compromised as result of increased BLIMP-1 expression

Summary

Introduction

Toxoplasma gondii, an Apicomplexan with broad geographical representation, can cause severe infection of the central nervous system (Torgerson et al, 2014). A number of other studies have confirmed the dominant role of CD8 T cells in long-term immunity against T. gondii infection, which is important to keep the chronic infection under control (Gazzinelli et al, 1992; Khan et al, 1994; Khan and Kasper, 1996).

Results

Conclusion