Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals

Johanna Tauriainen,Annika C Karlsson,Michael R Betts,Anders Sönnerborg,Gustavo Reyes-Terán,Ole Lund,Lydia Scharf,Steven G Deeks,Frederick M Hecht,Juliet Frederiksen,Marcus Buggert,Hans-Gustaf Ljunggren,Ali Naji

doi:10.1038/srep40354

Abstract

HIV-specific CD8+ T cells demonstrate an exhausted phenotype associated with increased expression of inhibitory receptors, decreased functional capacity, and a skewed transcriptional profile, which are only partially restored by antiretroviral treatment (ART). Expression levels of the inhibitory receptor, T cell immunoglobulin and ITIM domain (TIGIT), the co-stimulatory receptor CD226 and their ligand PVR are altered in viral infections and cancer. However, the extent to which the TIGIT/CD226/PVR-axis is affected by HIV-infection has not been characterized. Here, we report that TIGIT expression increased over time despite early initiation of ART. HIV-specific CD8+ T cells were almost exclusively TIGIT+, had an inverse expression of the transcription factors T-bet and Eomes and co-expressed PD-1, CD160 and 2B4. HIV-specific TIGIThi cells were negatively correlated with polyfunctionality and displayed a diminished expression of CD226. Furthermore, expression of PVR was increased on CD4+ T cells, especially T follicular helper (Tfh) cells, in HIV-infected lymph nodes. These results depict a skewing of the TIGIT/CD226 axis from CD226 co-stimulation towards TIGIT-mediated inhibition of CD8+ T cells, despite early ART. These findings highlight the importance of the TIGIT/CD226/PVR axis as an immune checkpoint barrier that could hinder future “cure” strategies requiring potent HIV-specific CD8+ T cells.

Highlights

During chronic HIV-1 infection CD8+ T cells gradually lose their cytotoxic function, production of antiviral cytokines and their capacity to proliferate[1,2,3,4]
TIGIT was expressed on all memory CD8+ T cell subsets but not on naïve CD8+ T cells, whereas PD-1 was more narrowly expressed on memory subpopulations within the central, effector, and transitional memory cells (Fig. 1d, and Supplementary Fig. S1)
This process has previously been linked to the co-expression of several inhibitory receptors, including PD-1, CD160, 2B4, TIM-3 and LAG-3 on CD8+ T cells[5,9,10], poor functionality[44,45] and an altered transcriptional profile[9]

Summary

Introduction

During chronic HIV-1 infection CD8+ T cells gradually lose their cytotoxic function, production of antiviral cytokines and their capacity to proliferate[1,2,3,4] (reviewed in ref. 5). These cells accumulate cell surface markers associated with immune dysfunction, e.g., inhibitory receptors such as PD-1, CD160, 2B4, TIM-3, and LAG-36–14 This pattern persists even after years of successful antiretroviral treatment (ART)[9,10]. HIV-specific cells display a specific pattern of T-box transcriptions factors (T-betdimEomeshi) that is coupled to the increased expression of inhibitory receptors[9] Together, these processes result in an exhausted population of HIV-specific CD8+ T cells that accumulates over time and impairs optimal control of the infection, even after successful ART. CD4+ T cells expressing TIGIT, alone or together with PD-1 and/or LAG-3 were shown to be enriched for persistent HIV during ART, suggesting that inhibitory receptor blockade treatment may have an effect on latently infected CD4+ T cells[26]. The expression of PVR on ex vivo CD4+ T cells from HIV-infected subjects has not been described

Methods

Results

Conclusion