Effects of IL-7 on Early Human Thymocyte Progenitor Cells In Vitro and in SCID-hu Thy/Liv Mice

Abstract

IL-7 is a critical component of thymopoiesis in animals and has recently been shown to play an important role in T cell homeostasis. Although there is increasing interest in the use of IL-7 for the treatment of lymphopenia caused by the HIV type 1, evidence that IL-7 may accelerate HIV replication has raised concerns regarding its use in this setting. We sought to identify the effects of IL-7 on human thymocyte survival and to determine the impact of IL-7 administration on in vivo HIV infection of the human thymus. Using in vitro analysis, we show that IL-7 provides potent anti-apoptotic and proliferative signals to early thymocyte progenitors. Analysis of CD34+ subpopulations demonstrates that surface IL-7 receptor is expressed on most CD34highCD5+CD1a− thymocytes and that this subpopulation appears to be one of the earliest maturation stages responsive to the effects of IL-7. Thus, IL-7 provides survival signals to human thymocytes before surface expression of CD1a. CD4+CD8+ thymocytes are relatively unresponsive to IL-7, although IL-7 protects these cells from dexamethasone-induced apoptosis. IL-7 has a predominantly proliferative effect on mature CD4+CD3+CD8− and CD8+CD3+CD4− thymocytes. In contrast to the in vitro findings, we observe that in vivo administration of IL-7 to SCID-hu Thy/Liv mice does not appear to enhance thymocyte survival nor does it appear to accelerate HIV infection. Given the growing interest in the use of IL-7 for the treatment of human immunodeficiency, these findings support additional investigation into its in vivo effects on thymopoiesis and HIV infection.

IL-7 Gene Therapy in Aging Restores Early Thymopoiesis without Reversing Involution

“…Our results are in line with those of Mertsching et al (48), who did not find any increase in either TCR ␣ or ␤ gene rearrangements during thymocyte ontogeny in high copy number IL-7 transgenic mice, which might be expected to have increased thymic output. In addition, human fetal thymus transplanted into scid mice did not display any increased thymopoiesis in the presence of exogenous IL-7 (19,21), despite an increase in TRECs within the transplant itself. Reports that IL-7 stimulates proliferation of pre-T cells but actually inhibits the development of mature T cells are also in line with our findings (49,50), but these studies were conducted using fetal thymus.…”

To kill or be killed: how HIV exhausts the immune system

“…IL-7 is a critical component of thymopoiesis and it has recently been shown to play an important role in T-cell homeostasis. In vitro, IL-7 provides potent antiapoptotic and proliferative signals to early thymocyte progenitors, mainly single positive 152 The contribution of IL-7 to thymic Tcell regeneration has been indicated by experiments using thymic organ culture systems, in which exogenous IL-7: (1) increased the frequency of TRECs in fetal, as well as infant, thymi, indicating that increased rearrangement of a TCRs had occurred; 153 (2) together with SDF-1, it enhanced the viability of CD34 þ T-cell precursors, by modulating the expression of Bcl-2 and Bax, and stimulated their proliferation. 153 In macaques infected with SIV, IL-7 induces both central renewal and a peripheral expansion of T lymphocytes associated with cell activation, without increasing the viral load.…”

Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques

“…Interleukin 7 (IL-7), the cytokine that promotes precursor B-and T-cell maturation [1][2][3] and sustains peripheral T-cell homeostasis, [4][5][6] is currently in phase 1/2 trials in diseases characterized by persistent lymphopenia. Although interim results from these investigations tentatively support the efficacy of this molecule in producing long-term T-cell increases in patients, an unexpectedly strong T-cell depletion was observed in all treated patients during day 1 of therapy 7 (Irini Sereti, National Institute of Allergy and Infectious Diseases, personal oral communication, June 2008).…”