title: 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.
authors: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA.
authors: Fabio E
authors: FE
authors: Leal
authors: Lishomwa C
authors: LC
authors: Ndhlovu
authors: Aaron M
authors: AM
authors: Hasenkrug
authors: Fernanda R
authors: FR
authors: Bruno
authors: Karina I
authors: KI
authors: Carvalho
authors: Harry
authors: H
authors: Wynn-Williams
authors: Walter K
authors: WK
authors: Neto
authors: Sabri S
authors: SS
authors: Sanabani
authors: Aluisio C
authors: AC
authors: Segurado
authors: Douglas F
authors: DF
authors: Nixon
authors: Esper G
authors: EG
authors: Kallas
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000032:analysis*; D001081:Apyrase / Q000032:analysis*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D005260:Female; D015490:HTLV-I Infections / Q000276:immunology* / Q000473:pathology; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D015703:Antigens, CD; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D001081:Apyrase; C067869:CD39 antigen