Expansion in CD39⁺ CD4⁺ 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; p. e2028
• 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: United States Public Library of Science 2013; Public Library of Science (PLoS)
• Subjects: Adult; Antigens, CD - analysis; Apyrase - analysis; CD4-Positive T-Lymphocytes - chemistry; CD4-Positive T-Lymphocytes - immunology; Colleges & universities; Cytokines; Disease; Expansion; Female; HIV; HTLV-I Infections - immunology; HTLV-I Infections - pathology; Human immunodeficiency virus; Humans; Interleukin-2 Receptor alpha Subunit - analysis; Lymphocytes; Male; Medicine; Middle Aged; Pathogenesis; T-Lymphocyte Subsets - chemistry; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - immunology; Th17 Cells - immunology; Tropical diseases; T-Lymphocyte Subsets; Interleukin-2 Receptor alpha Subunit; Humans; Middle Aged; Male; HTLV-I Infections; T-Lymphocytes, Regulatory; Adult; Apyrase; Female; CD4-Positive T-Lymphocytes; Th17 Cells; Antigens, CD
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0002028

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.