Expansion in CD39 ⁺ CD4 ⁺ Immunoregulatory T Cells and Rarity of Th17 Cells in HTLV-1 Infected Patients Is Associated with Neurological Complications

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 develops HAM/TSP. CD4 ⁺ T cells are the main target of infection and play a pivotal role in regulating immunity to HTLV and are hypothesized to participate in the pathogenesis of HAM/TSP. The CD39 ectonucleotidase receptor is expressed on CD4 ⁺ T cells and based on co-expression with CD25, marks T cells with distinct regulatory (CD39 ⁺CD25 ⁺) and effector (CD39 ⁺CD25 ⁻) function. Here, we investigated the expression of CD39 on CD4 ⁺ T cells from a cohort of HAM/TSP patients, HTLV-1 asymptomatic carriers (AC), and matched uninfected controls. The frequency of CD39 ⁺ CD4 ⁺ T cells was increased in HTLV-1 infected patients, regardless of clinical status. More importantly, the proportion of the immunostimulatory CD39 ⁺CD25 ⁻ CD4 ⁺ T-cell subset was significantly elevated in HAM/TSP patients as compared to AC and phenotypically had lower levels of the immunoinhibitory receptor, PD-1. We saw no difference in the frequency of CD39 ⁺CD25 ⁺ regulatory (Treg) cells between AC and HAM/TSP patients. However, these cells transition from being anergic to displaying a polyfunctional cytokine response following HTLV-1 infection. CD39 ⁻CD25 ⁺ T cell subsets predominantly secreted the inflammatory cytokine IL-17. We found that HAM/TSP patients had significantly fewer numbers of IL-17 secreting CD4 ⁺ T cells compared to uninfected controls. Taken together, we show that the expression of CD39 is upregulated on CD4 ⁺ T cells HAM/TSP patients. This upregulation may play a role in the development of the proinflammatory milieu through pathways both distinct and separate among the different CD39 T cell subsets. CD39 upregulation may therefore serve as a surrogate diagnostic marker of progression and could potentially be a target for interventions to reduce the development of HAM/TSP.

Author Summary

Human T-lymphotropic virus type 1 (HTLV-1) has been estimated to infect 10–20 million worldwide. The majority of infected individuals are asymptomatic, however, 2% to 3% develop a neurodegenerative disorder called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The reasons why persons with HTLV-1 develop these complications appear to be multiple and complex. Cellular immune response has been implicated in the development of inflammatory alterations in these patients, however the pathogenic mechanisms for disease progression remain unclear. Regulatory CD4 ⁺ T cells (Treg) and Th17 cells derive from a common progenitor and conflicting results regarding frequency and function are found in the development of HAM/TSP. The expression of the CD39 ectoenzyme, a molecule that can mediate immunostimulatory and inhibitory effects, is useful to define IL-17 secreting cell populations, suppressive CD4 ⁺ T cells and CD4 ⁺ T cells with immunostimulatory properties. The interplay of these T-cell subsets may reveal important aspects of HAM/TSP pathogenesis. In this study, we performed an evaluation of the immunoregulatory CD4 ⁺ T-cell subsets defined by CD39 expression including Th17 cells. Our results present phenotypic and functional alterations in the CD4 ⁺ T cell profile that could account for the transition from asymptomatic status to HAM/TSP, predicting clinical disease risk and tracking disease progression.