Background:  Interleukin-7 (IL-7) is crucial in the extra-thymic maintenance of the naïve CD4⁺ T-cell subset. IL-7 acts via the IL-7 receptor (IL-7R) which consists of a specific a-chain (CD127) dimerised to the cytokine common g-chain (CD132). Plasma levels of IL-7 are elevated in HIV-1 infection and inversely correlate to total and naïve CD4⁺ T-cell counts. The effect of elevated IL-7 on cellular expression of CD127 and CD132 in vitro or in vivo remains unknown. We hypothesise that IL-7R components are down-regulated in the presence of elevated IL-7 levels.

Methods:  PBMC isolated from healthy volunteers were cultured with IL-7 (0 to 10 ng/mL) for 7 days in vitro. In a subset of cultures protein synthesis was inhibited using cyclohexamide (50 µM). CD127 mRNA expression was analysed by RT-PCR. Ex vivo surface and intracellular CD127 and CD132 expression were determined by flow cytometry on cryopreserved PBMC from healthy volunteers (n = 5), and patients with primary (PHI; n = 5) and chronic (CHI; n = 5) HIV infection prior to and after 10 months of anti-retroviral therapy. Differences between groups were analysed using the Mann-Whitney test.

Results:  In vitro addition of IL-7 resulted in a dose-dependant decrease in surface CD127 but not CD132. This down-regulation was not accompanied by a reduction in CD127 mRNA expression, or production of truncated variants. Intracellular staining revealed negligible CD127 but considerable CD132 expression. Down-regulation of CD127 was reversed after removal of exogenous IL-7 and re-expression was dependent on de novo protein synthesis. Ex vivo, there was down-regulation of CD127 but not CD132 expression on both naïve and memory CD4⁺ T-cells in HIV infected subjects (the table):

      Decreased median CD127 expression on CD4⁺ T-cell subsets in HIV-1 infection

* p<0.05; **p<0.01 Compared to healthy volunteers

Conclusions:  Elevated IL-7 decreases CD127 but not CD132 expression in vitro and in vivo. This down-regulation is a post transcription event. Investigating the process by which CD127 is lost from CD4⁺ T-cell subsets may provide insight into the dysregulation of T-cell homeostasis observed in HIV infection.

Keywords: IL-7; IL-7R; CD4+ T-cell