title: NKp44L expression on CD4+ T cells is associated with impaired immunological recovery in HIV-infected patients under highly active antiretroviral therapy.
abstract: OBJECTIVE
  HIV-infected immunological nonresponders (InRs) patients fail to show satisfactory CD4+ T-cell recovery despite virologically effective HAART. We propose that NKp44L, the cellular ligand of an activating natural killer (NK) receptor, expressed only on uninfected bystander CD4+ T cells from HIV-1 infected patients, could play a major role in this phenomenon by sensitizing these cells to NK killing.
  
  
  METHODS
  Phenotype and multifunctional status of CD4+ T cells, especially the subsets expressing and not expressing NKp44L, were characterized for HIV-infected patients receiving HAART for at least 2 years, during which their viral load remained less than 40 copies/ml; 53 were InRs (CD4 cell count always <350 cells/µl), and 82 immunological responders (CD4 cell count always ≥350 cells/µl). Flow cytometry determined NKp44L expression in association with specific markers of proliferation, maturation, activation, homeostasis, and intracellular cytokine production. Degranulation of NKp44+ determined the functional capacity of NK cells.
  
  
  RESULTS
  InRs exhibited high levels of NKp44L+CD4+ T cells. Compared with NKp44L negative cells, the frequency of naive CD45RA+CCR7+ T cells expressing NKp44L fell (P < 0.001) and their proliferative capacity grew. Moreover, apoptosis and a unique ability to produce multiple cytokines (IL-2, IFN-γ, and TNF-α) without or after phytohemagglutinin or anti-CD3/CD28 stimulation distinguished NKp44L+ T cells.
  
  
  CONCLUSIONS
  InR status is associated to a significant expansion of highly differentiated, multifunctional and apoptotic CD4+ T cells expressing NKp44L. This could explain a rapid CD4+ T-cell turnover in InR preventing immune recovery. These data suggest a new target for developing therapeutic strategies to prevent NKp44L expression and then stimulating immune recovery in InRs.
authors.forename: Alexis
authors.initials: A
authors.lastname: Sennepin
authors.forename: Florence
authors.initials: F
authors.lastname: Baychelier
authors.forename: Amélie
authors.initials: A
authors.lastname: Guihot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Nel
authors.forename: Raphaël
authors.initials: R
authors.lastname: Ho Tsong Fang
authors.forename: Ruxandra
authors.initials: R
authors.lastname: Calin
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Anne
authors.initials: A
authors.lastname: Simon
authors.forename: Joël
authors.initials: J
authors.lastname: Crouzet
authors.forename: Patrice
authors.initials: P
authors.lastname: Debré
authors.forename: Vincent
authors.initials: V
authors.lastname: Vieillard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry* / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000032:analysis*
chemical_list: C112837:NCR2 protein, human; D055629:Natural Cytotoxicity Triggering Receptor 2