Expansion in [CD39.sup.+] [CD4.sup.+] immunoregulatory T cells and rarity of Th17 cells in HTLV-1 infected patients is associated with neurological complications

• Published in: PLoS neglected tropical diseases Vol. 7; no. 2
• Main Authors: Leal, Fabio E, Ndhlovu, Lishomwa C, Hasenkrug, Aaron M, Bruno, Fernanda R, Carvalho, Karina I, Wynn-Williams, Harry, Neto, Walter K, Sanabani, Sabri S, Segurado, Aluisio C, Nixon, Douglas F, Kallas, Esper G
• Format: Journal Article
• Language: English
• Published: Public Library of Science 01.02.2013
• Subjects: Gene expression; Genetic aspects; HTLV infections; Immune response; Regulation; T cells
• ISSN: 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0002028

HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV- 1associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develops HAM/TSP. [CD4.sup.+] 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.sup.+] T cells and based on co-expression with CD25, marks T cells with distinct regulatory ([CD39.sup.+][CD25.sup.+]) and effector ([CD39.sup.+][CD25.sup.-]) function. Here, we investigated the expression of CD39 on [CD4.sup.+] T cells from a cohort of HAM/TSP patients, HTLV-1 asymptomatic carriers (AC), and matched uninfected controls. The frequency of [CD39.sup.+][CD4.sup.+] T cells was increased in HTLV-1 infected patients, regardless of clinical status. More importantly, the proportion of the immunostimulatory [CD39.sup.+][CD25.sup.-][CD4.sup.+] 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.sup.+][CD25.sup.+] 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.sup.-][CD25.sup.+] 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.sup.+] T cells compared to uninfected controls. Taken together, we show that the expression of CD39 is upregulated on [CD4.sup.+] 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.