Differential effects of Interleukin-7 on normal and HIV-modified T-cell development

Abstract

In this study, an organ culture chimera system was used to study the physiological role of Interleukin-7 (IL-7) in normal T cell development by antibody neutralization of cytokine activity. Additionally, the effect of IL-7 on HIV-modified T cell development was studied. When chimeras were treated with anti-IL-7 for 3 day intervals, a differential effect was observed. Early in culture, when the majority of the cells are CD4/CD8/CD3 triple negative (TN), anti-IL-7 decreased the number of immature and mature cells. The CD44⁺CD25⁺ TN cells were not able to make the transition to the CD44⁻CD25⁺ TN stage without IL-7. In contrast, when IL-7 is neutralized later in the culture period, when the majority of cells are in the double positive (DP) or mature single positive (SP) stages, the number of CD3⁺ cells increases. These data suggest that in addition to its capacity to maintain the viability of the immature cells, IL-7 may actually hold the cells in the immature state. It has been suggested that HIV infection affects the ability to regenerate new T cells. Peripheral blood mononuclear cells (PBMC) from HIV-infected patients and uninfected controls were used as donor cells. The number of mature CD4, CD8 and CD4/8 double positive (DP) cells generated in the cultures derived from HIV-infected PBMC was diminished. This lack of development occurred even with blood from donors with a CD4 count of 1,000/μL. Limit dilution experiments showed that the number of functional precursors in HIV-infected patients is lower than in uninfected patients. The CD3⁻ CD8⁺ and DP T cells were not reduced unless the CD4 count was <250/ml. These data suggest that there is a block in T cell development at the DP stage in cultures derived from PBMC with CD4 counts. IL-7 treatment resulted in a greater loss in the number of T cells produced by infected PBMC. These data show that while IL-7 plays a critical role in normal T cell development, it has the potential to increase the T cell depletion of HIV-infected individuals.