Science Spotlight

Regulatory T cells: friends and foes in herpes infections

Human genital skin biopsies from acute time-point of HSV-2 reactivation (left panel), from the same location at two weeks post healing (middle panel) and from the arm (right panel). Tregs were visualized by a staining for CD4 (red) and Foxp3 (green).
Figure provided by Dr. Neta Milman

Last month, Science Spotlight covered an article on the importance of regulatory T cells (Tregs) in guiding the response to herpes simplex virus-2 (HSV-2). In particular, lack of Tregs resulted in an impaired T-cell priming in a mouse model of HSV-2 infection (Soerens A., Mucosal Immunol 2016). Tregs though have a dual nature: they do not only help build an efficient immune response in the early phases of several viral infections, but also suppress the immune response in homeostatic conditions to avoid autoimmunity, and after the resolution of an infection to avoid immune pathology.

While Tregs help build the early immune response to HSV-2, their role during reactivation is unknown. In humans, HSV-2 undergoes frequent reactivation that results in asymptomatic or symptomatic episodes, which manifest as ulcerations. During reactivation, T cell influx helps control the infection (Zhu J., J Exp Med 2007, and Johnston C., J Virol 2014), and the contemporary presence of Tregs could impair such a response. A group of Fred Hutch and University of Washington researchers investigated this issue by quantifying Tregs and characterizing their functions in herpetic lesions of HSV-2 infected subjects at the onset of an acute symptomatic lesion, 5-7 days later (healed time point) and 2,4, and 8 weeks after healing. The results of this study have been published in the May issue of the Journal of Infectious Diseases.

Tregs, identified by the expression of CD4 and of their master transcription factor FoxP3, were detected in HSV-2 lesions, and expressed high levels of the known Treg markers CD25 and CTLA-4, and low levels of CD127. Moreover, they expressed the memory marker CD45RO, and a fraction of them resulted positive for the skin-homing molecule cutaneous lymphocyte antigen (CLA). Interestingly, the kinetic of tissue accumulation of Tregs showed the same pattern as that observed for T cells, peaking at the time of ulceration and decreasing over time. If Treg were solely involved in switching-off the immune response after the resolution of the reactivation, a later increase of Tregs, as compared to T cells, would be expected. This observation supports a ‘foe’ role of Tregs in HSV-2 reactivation. This hypothesis is further supported by the observed direct correlation between Treg frequency and viral titer.  Moreover, Tregs spatial localization mirrored the one observed for T cells, with clusters of Tregs present in the upper dermis during acute lesions and at the dermal-epidermal junction at the time of healing. Two weeks post healing, low densities of Tregs persisted near the dermal-epidermal junction, where HSV-2 specific memory CD8 T cells, implicated in immune surveillance, reside. Finally, the ratios between Treg and ‘conventional’, FoxP3 negative CD4+ T cells, and Tregs and CD8+ T cells were higher during virological reactivation as compared to quiescence.

Dr. Milman, first author of the study and former Fred Hutch postdoc, suggests a clinical application of the study: "Our finding that higher regulatory to effector T cells ratios were found in biopsies where viral shedding was detected, imply that increased densities of Tregs may dampen immune effector function and affect lesion severity.  This suggests that inhibiting Tregs may improve healing times and create clinical benefits."

 The study was supported by the National Institutes of Health and the James B Pendleton Charitable Trust.

Milman N,Zhu J,Johnston C,Cheng A,Magaret A,Koelle DM,Huang ML,Jin L,Klock A,Layton ED,Corey L. 2016. In Situ Detection of Regulatory T Cells in Human Genital Herpes Simplex Virus Type 2 (HSV-2) Reactivation and Their Influence on Spontaneous HSV-2 Reactivation. J Infect Dis. Epub ahead of print. 


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