title: Elevated expression of LAG-3, but not PD-1, is associated with impaired iNKT cytokine production during chronic HIV-1 infection and treatment.
abstract: BACKGROUND
  LAG-3 is a potent negative regulator of the immune response but its impact in HIV infection in poorly understood. Unlike exhaustion markers such as PD-1, Tim-3, 2B4 and CD160, LAG-3 is poorly expressed on bulk and antigen-specific T cells during chronic HIV infection and its expression on innate lymphocyte subsets is not well understood. The aim of this study was to assess LAG-3 expression and association with cellular dysfunction on T cells, NK cells and iNKT cells among a cohort of healthy and HIV-infected female sex workers in Nairobi, Kenya.
  
  
  RESULTS
  Ex vivo LAG-3 expression was measured by multiparametric flow cytometry, and plasma cytokine/chemokine concentrations measured by bead array. Although LAG-3 expression on bulk T cells was significantly increased among HIV-infected women, the proportion of cells expressing the marker was extremely low. In contrast, LAG-3 was more highly expressed on NK and iNKT cells and was not reduced among women treated with ART. To assess the functional impact of LAG-3 on iNKT cells, iNKT cytokine production was measured in response to lipid (αGalCer) and PMA/Io stimulation by both flow cytometry and cytokine bead array. iNKT cytokine production is profoundly altered by both HIV infection and treatment, and LAG-3, but not PD-1, expression is associated with a reduction in iNKT IFNγ production.
  
  
  CONCLUSIONS
  LAG-3 does not appear to mediate T cell exhaustion in this African population, but is instead expressed on innate lymphocyte subsets including iNKT cells. HIV infection alters iNKT cytokine production patterns and LAG-3 expression is uniquely associated with iNKT dysfunction. The continued expression of LAG-3 during treatment suggests it may contribute to the lack of innate immune reconstitution commonly observed during ART.
authors: Jennifer A
authors: JA
authors: Juno
authors: Andrew T
authors: AT
authors: Stalker
authors: Jillian Lm
authors: JL
authors: Waruk
authors: Julius
authors: J
authors: Oyugi
authors: Makobu
authors: M
authors: Kimani
authors: Francis A
authors: FA
authors: Plummer
authors: Joshua
authors: J
authors: Kimani
authors: Keith R
authors: KR
authors: Fowke
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000378:metabolism*; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D064368:Healthy Volunteers; D054884:Host-Pathogen Interactions; D006801:Humans; D007630:Kenya; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D060386:Sex Workers; D015854:Up-Regulation; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein