title: Proliferation of weakly suppressive regulatory CD4+ T cells is associated with over-active CD4+ T-cell responses in HIV-positive patients with mycobacterial immune restoration disease.
abstract: The role of Treg in patients with late-stage HIV disease, who commence combination antiretroviral therapy (cART) and develop pathogen-specific immunopathology manifesting as immune restoration disease (IRD) remains unclear. We hypothesised that Treg could be defective in either numbers and/or function and therefore unable to ensure the physiological equilibrium of the immune system in patients with IRD. Phenotypic and functional CD4(+) T-cell subsets of eight late-stage HIV patients with nadir CD4 count <50 cells/microL, who developed mycobacterial IRD upon commencing cART were compared with six therapy naive HIV(+) patients (nadir CD4 count <50 cells/microL), who did not develop an IRD after cART. Mycobacterium-avium-specific CD4(+) T cells from IRD patients produced high levels of IFN-gamma and IL-2 compared with controls (p<0.001). Surprisingly, we found a significant expansion of CD127(lo)Foxp3(+)CD25(+) Treg in IRD patients and a higher ratio of Treg to effector/memory subsets (p<0.001). In vitro suppression assays demonstrated reduced functional capacity of suppressor cells and diminished IL-10 secretion in IRD patients. Plasma levels of IL-7 were increased in patients and, interestingly, exogenous IL-7 and other cytokines strongly inhibited Treg suppression. These data suggest that despite substantial Treg expansion in IRD, their ability to induce suppression, and thereby downregulate aberrant immune responses, is compromised.
authors.affiliation: Centre for Immunology, St Vincent's Hospital, Darlinghurst, NSW, Australia. n.seddiki@cfi.unsw.edu.au
authors.forename: Nabila
authors.initials: N
authors.lastname: Seddiki
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Sasson
authors.forename: Brigitte
authors.initials: B
authors.lastname: Santner-Nanan
authors.forename: Meeling
authors.initials: M
authors.lastname: Munier
authors.forename: David
authors.initials: D
authors.lastname: van Bockel
authors.forename: Susanna
authors.initials: S
authors.lastname: Ip
authors.forename: Debbie
authors.initials: D
authors.lastname: Marriott
authors.forename: Sarah
authors.initials: S
authors.lastname: Pett
authors.forename: Ralph
authors.initials: R
authors.lastname: Nanan
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.forename: John J
authors.initials: JJ
authors.lastname: Zaunders
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000150:complications / Q000276:immunology* / Q000382:microbiology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D015851:Interleukin-7 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009161:Mycobacterium / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014376:Tuberculosis / Q000150:complications / Q000276:immunology*
chemical_list: C508598:IL4 protein, human; C508600:IL6 protein, human; C508605:IL7 protein, human; D015850:Interleukin-6; D015851:Interleukin-7; D015847:Interleukin-4; D007371:Interferon-gamma