MAIT cells are reduced in frequency and functionally impaired in human T lymphotropic virus type 1 infection: Potential clinical implications.

Dominic Paquin-Proulx,Emanuela A S Costa,Benjamin C Greenspun,Douglas F Nixon,Esper G Kallas,Fabio E Leal,Aluisio C Segurado,Katalin Andrea Wilkinson

doi:10.1371/journal.pone.0175345

Abstract

HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develop HAM/TSP. The cellular immune response has been implicated in the development of inflammatory alterations in these patients; however the pathogenic mechanisms for disease progression remain unclear. Furthermore, HTLV-1-infected individuals have an increase incidence of Mycobacterium tuberculosis (Mtb) infection, suggesting that immunological defect are associated with HTLV-1 infection. Evidence suggests an important role for Mucosal-associated invariant T (MAIT) cells in the early control of Mtb infection. Chronic viral infections like HIV and HCV have been associated with decreased frequency and functionality of MAIT cells. We hypothesized that HTLV-1 infection is associated with similar perturbations in MAIT cells. We investigated MAIT cell frequency, phenotype, and function by flow cytometry in a cohort of 10 asymptomatic and 10 HAM/TSP HTLV-1 infected patients. We found that MAIT cells from HTLV-1-infected subjects were reduced and showed high co-expression of the activation markers CD38 and HLA-DR but normal levels of CCR6 and CD127. MAIT cells had a lower expression of the transcription factor PLZF in HAM/TSP patients. Unlike Tax-specific CD8+T cells, which are hyperfunctional, MAIT cells from HTLV-1-infected subjects had a poor IFNγ response following antigen stimulation. MAIT cell perturbations in HTLV-1 infection were not associated with HTLV-1 proviral load and MAIT cells were not infected by HTLV-1 in vivo. Rather, MAIT cells loss was associated with immune activation. Overall, our results do not support a role for MAIT cells in HAM/TSP pathogenesis but reduced numbers of MAIT cells, together with their poor functionality, could contribute to the increased susceptibility of HTLV-1-infected individuals to other infectious agents.

Highlights

Human T-lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus estimated to infect around 10 million people worldwide[1], with no clinical evidence of infection in the majority of carriers
Elevated co-expression of CD38 and HLA-DR was found on CD8 T cells of HTLV-1-infected individuals but no difference was observed between asymptomatic carriers and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) patients (Fig 2C and 2D)
We evaluated the expression of the exhaustion marker PD-1 and did not observe any significant difference between controls and HTLV-1-infected subjects or between asymptomatic carriers and HAM/TSP patients (S2 Fig)

Summary

Introduction

Human T-lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus estimated to infect around 10 million people worldwide[1], with no clinical evidence of infection in the majority of carriers. The life-long risk of developing HTLV-1-associated pathology is approximately 10%, while 0.3 to 4% of HTLV-1 carriers will present a neurodegenerative disorder with clinical similarities to Multiple Sclerosis (MS) called HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP)[2]. HTLV-1 is the causative agent of an aggressive type of lymphoproliferative disorder called Adult T-cell leukemia[7]. The role of the various T-cell subsets in the immune response to infection HTLV-1 and how it influences the control or the development of disease is not fully understood

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Conclusion