Dysregulated IL-21-mediated phosphorylation and nuclear translocation of STAT3 in B-cells of HIV-infected individuals may be associated with increased IFN-α activity — ASN Events
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  3. Dysregulated IL-21-mediated phosphorylation and nuclear translocation of STAT3 in B-cells of HIV-infected individuals may be associated with increased IFN-α activity

Dysregulated IL-21-mediated phosphorylation and nuclear translocation of STAT3 in B-cells of HIV-infected individuals may be associated with increased IFN-α activity (#180)

Lilian Cha 1 , Martyn A French 1 2 3 , Sonia Fernandez 1
  1. Medical School and School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia
  2. Medical School, University of Western Australia, Perth, Western Australia, Australia
  3. Department of Clinical Immunology, Royal Perth Hospital, Perth, Western Australia, Australia

B-cell dysfunction, including a decrease in both the magnitude and isotype diversification of IgG antibody responses, is observed in HIV-infected individuals. Given that interleukin (IL)-21 is an essential regulator of B-cell differentiation into antibody-secreting cells, defects in the IL-21 signalling pathway, including STAT3, may be occurring. As interferon (IFN)-α has been implicated in HIV-induced B-cell dysfunction, the aim of this study was to compare IL-21 induced phosphorylation and nuclear translocation of STAT3 in B-cell subsets from HIV patients and seronegative controls, and assess the effect of IFN-α upon this pathway.

Thirty HIV-1 infected patients and ten HIV seronegative controls were recruited. HIV-1 infected patients comprised both antiretroviral therapy (ART)-naïve (n=10) and ART-treated (n=20) patients. Peripheral blood mononuclear cells (PBMC) were stimulated with 50ng/mL IL-21 for 15 minutes. In a subset of controls, PBMC were additionally pre-cultured in the absence or presence of IFN-α2b. Phosphorylation and nuclear translocation of STAT3 was assessed in naïve (CD20+ CD27-) and memory (CD20+ CD27+) B-cells by flow cytometry.

Frequencies of phosphorylated (p)STAT3+ total B-cells were significantly lower in ART-naïve patients compared to controls (p=0.003) and ART-treated patients (p=0.03). When naïve and memory B-cells were assessed separately, these differences were only evident within the naïve B-cell subpopulation. Similarly, the proportions of pSTAT3+ naïve B-cells exhibiting nuclear translocation were lower in ART-naïve patients compared to controls (p=0.009) and ART-treated patients (p=0.01). These differences were not evident in the memory B-cell subpopulation. IFN-α2b increased pSTAT3 in naïve B-cells (p=0.002) but decreased pSTAT3 in memory B-cells (p=0.002). IFN-α2b also inhibited pSTAT3 translocation in naïve B-cells only (p=0.02).

IL-21-mediated phosphorylation and nuclear translocation of STAT3 is perturbed in B-cells of HIV patients and increased IFN-α activity may be responsible. This could contribute to B-cell dysfunction in HIV infection and the subsequent generation and maintenance of long-term humoral immune memory.

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