In Vitro HIV Type 1 Infection Indirectly Alters CD127 Expression on CD8⁺ T Cells

Abstract

Decreased expression of interleukin (IL)-7 receptor a (CD127) on CD8 + T cells in progressive HIV disease suggests a role for CD127 regulation in HIV immunopathogenesis. The direct effect of HIV on CD127 expression has not been explored to explain these in vivo findings. Peripheral blood mononuclear cells (PBMCs) or isolated CD8 + T cells from healthy individuals were cultured with either X4 (HIV-1 IIIB ), R5 (HIV-1 BaL ), dual tropic (HIV-1 CS204 ), or replication-incompetent (HIV 8E5 ) strains of HIV. Both X4 and R5 strains transiently decreased CD127 expression on CD8 + T cells in PBMC cultures but had no effect on isolated CD8 + T cell cultures. Isolated CD8 + T cells exposed to either (1) PBMCs incubated with HIV and cultured in a transwell or (2) supernatants from PBMCs incubated with HIV resulted in decreased CD127 expression. Under no conditions did the replicationincompetent HIV strain affect CD127 expression. As observed in vivo, infection of PBMCs with HIV in vitro results in the downregulation of CD127 surface expression on CD8 + T cells. Collectively, these data indicate that soluble factor(s) released as a result of HIV infection regulate CD127 expression. Further elucidation of the mechanism(s) of CD127 downregulation will provide important insights into the immunopathogenesis of HIV disease.

Generalized Liver- and Blood-Derived CD8+ T-Cell Impairment in Response to Cytokines in Chronic Hepatitis C Virus Infection

“…To investigate activation of the Jak/STAT pathway in response to IL-7 in health and chronic HCV infection, the phosphorylation of STAT5 (pSTAT5) was evaluated in CD8 + T-cells. Phosphorylation of STAT5 in response to IL-7 (0.01-10ng/ml) occurred in a dose dependent manner in CD8 + T-cells isolated from HCV - controls and HCV-infected individuals (one-way ANOVA p<0.0001 and p = 0.0003, respectively), as expected [ 32 , 42 ] ( Fig 2A and 2B ). Upon IL-7 stimulation, the minimum, and physiological, concentration of IL-7 required for a significant increase in pSTAT5 was lower for controls (0.1ng/ml) than in HCV infection (1ng/ml) (p≤ 0.05, Dunnett post-test).…”

“…To quantify IL-7-mediated proliferation of blood-derived CD8 + T-cells, CFSE-labelled cells were stimulated with suboptimal amounts of T-cell mitogen (PHA, 0.2 ug/ml), since T-cell activation is required to enable human T-cells to proliferate in response to IL-7 [ 43 ]. Cells were cultured with a dose of IL-7 known to induce detectible cell division (10ng/ml) [ 42 ]. There was minimal proliferation of cells following culture with IL-7 or PHA alone, while IL-7 + PHA induced multiple cell divisions (%CFSE low cells) ( Fig 3A and 3B ).…”

“…This was not associated with lower CD127 expression as only T CM cells had a lower CD127 ( Fig 1F ). The proliferation of CD8 + T-cells induced by IL-7 was similar between controls and HCV infection ( Fig 3C ), unlike HIV infection [ 42 ]. The activation of STAT5 is also associated with T-cell proliferation, however activation of the Akt pathway may have compensated for the inadequacies of STAT5 signaling in this instance, although our experimental efforts could not reliably assess Akt activity in these samples [ 54 ].…”

“…This suggests an inherent cell deficiency similar to that of dysfunctional CD8 + CD127 + T-cells in HIV-infected individuals (e.g. reduced IL-7 signalling, survival and proliferation) [ 42 , 45 ], contrasted in part by the marked decrease of CD127 expression on bulk CD8 + T-cells in HIV infection [ 46 – 49 ]. In addition, receptor expression was not associated with age in HCV infection, unlike in HIV infection [ 50 ].…”

Expression of γ‐chain cytokine receptors on CD8+ T cells in HIV infection with a focus on IL‐7Rα (CD127)

“…56,57,66 This suggests that ongoing HIV replication either directly or indirectly downregulates CD127 on the majority of CD8 + T cells, as recently observed in vitro. 82 Given the importance of IL-7/IL-7R in mediating CD8 + T-cell function, its impairment may be a major reason for observed CD8 + T-cell dysfunction observed in HIV infection. 3,4 Another g C cytokine whose production is increased in HIV infection is IL-4.…”