HIV infection of thymocytes inhibits IL-7 activity without altering CD127 expression

Abstract

BackgroundThymic function is altered in HIV infection and characterized by dysregulation of the thymic epithelial network, reduced thymic output and ultimately an impaired naïve T-cell pool. The IL-7/IL-7 receptor (IL-7R) signalling pathway is critical for the maturation and differentiation of thymocytes. HIV infection is associated with a decrease in IL-7Rα (CD127) expression and impaired CD127 signalling in circulating CD8+ T-cells; however, little is known about the effect of HIV on CD127 expression and IL-7 activity in the thymus. Therefore, the effect of in vitro HIV infection on CD127 expression and IL-7-mediated function in thymocytes was investigated.FindingsIn vitro HIV infection of thymocytes did not affect CD127 expression on either total thymocytes or on single positive CD4 or single positive CD8 subsets. However, HIV infection resulted in a decrease in the level of IL-7-induced STAT-5 phosphorylation and Bcl-2 expression in unfractionated thymocytes.ConclusionThese findings indicate that HIV infection alters IL-7 responsiveness of thymocytes by a mechanism other than CD127 downregulation and potentially explain the disruption in thymopoiesis observed in HIV infection.

IL‐7 induces sCD127 release and mCD127 downregulation in human CD8+ T cells by distinct yet overlapping mechanisms, both of which are impaired in HIV infection

“…In the present study, despite the high level of CD127 expression on CD8 + T cells that accompanied long-term effective HAART, CD8 + T cells derived from HIV+ individuals were less responsive to IL-7 with respect to downregulation of mCD127 and induction of sCD127. This decreased sensitivity of CD8 + T cells from effectively treated HIV+ individuals is in line with previous work from our group [32]. Since CD132 is constitutively expressed and has even been shown to be upregulated on T cells from HIV+ patients [7], any reduction in IL-7 response is unlikely due to lack of the IL-7R complex.…”

“…In concordance with these results, subsequent studies in humans have reported the presence of a more robust CD8 + T cell response in HIV nonprogressors [25][26][27]. We and others have shown that, in the face of their importance in controlling viral replication, CD8 + T cells, as well as thymocytes and Th17 cells, retain impaired responsivity to IL-7 in virally suppressed HIV-infected individuals [28][29][30][31][32].…”

An In vitro Model for the Study of HIV Infection of Thymocytes

“…Thymocytes were infected in vitro with a clinical isolate HIV cs204 following previously described methods [26]. Briefly, prior to infection, thymocytes were resuspended to a concentration of 2x10 6 cells/ml in McCoys 5A media with polybrene (Sigma-Aldrich) (3 μg/ml) for 1 hour at 37ºC.…”

Growth hormone in the presence of laminin modulates interaction of human thymic epithelial cells and thymocytes in vitro

“…The role of IL-7 in thymopoiesis is multifaceted, promoting thymocyte proliferation and survival by upregulating anti-apoptotic protein Bcl-2 and downregulating pro-apoptotic protein Bax [ 34 ]. GH can modulate genes committed to distinct biological activities of thymic epithelial cells, including expression of this cytokine [ 35 ].…”