IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates

Abstract

Interleukin-7 (IL-7) is important for thymopoiesis in mice and humans because IL-7 receptor ␣ (IL-7R␣) mutations result in a severe combined immunodeficiency phenotype with severe thymic hypoplasia. Recent evidence has indicated that IL-7 also plays an important role as a regulator of T-cell homeostasis. Here we report the immunologic effects of recombinant human IL-7 (rhIL-7) therapy in normal and simian immunodeficiency virus (SIV)-infected nonhuman primates. Cynomolgus monkeys receiving 10 days of rhIL-7 showed substantial, reversible increases in T-cell numbers involving a dramatic expansion of both naive and nonnaive phenotype CD4 ؉ and CD8 ؉ subsets. Although IL-7 is known to have thymopoietic effects in mice, we observed marked declines in the frequency and absolute number of T-cell receptor excision circlepositive (TREC ؉ ) cells in the peripheral blood and dramatic increases in the percentage of cycling T cells in the peripheral blood as measured by Ki-67 expression (baseline less than 5% to approximately 50% after 6 days of therapy) and ex vivo bromodeoxyuridine (BrdU) incorporation. Similarly, moderately CD4-depleted SIV-infected macaques treated with rhIL-7 also had significant increases in peripheral blood CD4 ؉ and CD8 ؉ T cells following rhIL-7 therapy. Thus, rhIL-7 induces dramatic alterations in peripheral T-cell homeostasis in both T-cellreplete and T-cell-depleted nonhuman primates. These results further implicate IL-7 as a promising immunorestorative agent but illustrate that a major component of its immunorestorative capacity reflects effects on mature cells. These results also raise the possibility that IL-7 therapy could be used to temporarily modulate Tcell cycling in vivo in the context of immunotherapies such as vaccination. (Blood. 2003;

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

“…In SIV-infected macaques, IL-7 induced the proliferation of naive T cell subsets within the CD4 ϩ and CD8 ϩ T cell populations that acquire a "memory-like" phenotype as previously described both in mice and macaques (28,59) (data not shown), impairing our ability to properly quantitate T cell subsets following IL-7 treatment. In contrast, IL-15 mainly increased the Ki-67 marker on CD4 ϩ and CD8 ϩ effector memory T cells (Fig.…”

“…Both IL-7 and IL-15 are cytokines produced by stromal cells that directly affect the homeostatic proliferation of memory T cells and regulate effector function (63,64). Prior studies on naive or SIV-infected macaques treated with rIL-7 protein have demonstrated that this cytokine alters T cell homeostasis (27,28,65) without altering SIV replication (66). The use of rIL-15 has been pioneered in naive macaques alone or together with Ags (26) and has been demonstrated to increase the frequency of long-lived CD4 ϩ and CD8 ϩ T cells.…”

“…In uninfected macaques immunized with tetanus toxoid or a live flu vaccine, rIL-15 increased long-term memory responses (26). In contrast, the administration of rIL-7 to healthy or SIV-infected macaques increased the proliferation of all T cell subsets and enhanced de novo thymic production (27)(28)(29).…”

“…IL-7 was maintained during the first week of vaccination to favor the expansion of memory cells, as we had previously observed that IL-7 at 100 g/kg increased the proliferation of memory T cell subsets in addition to naive cells (28,29). Because murine studies indicate that IL-15 is important for both the initiation and maintenance of immune responses (18), this cytokine was administered at the time of immunization and maintained for three consecutive weeks.…”

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

“…Exogenous administration of IL-15 or induction of host expression of IL-15 in wildtype mice by reagents, such as poly I:C, lipopolysaccharide (LPS) and type I-IFNs, causes a selective increase in the proliferation of CD8 + CD44 high T cells in vivo [29][30][31]. Exogenous administration of IL-7 to mice enhances T-cell number and function [32,33] and, in both intact and immunodeficient non-human primates, causes a considerable yet reversible increase in the circulating levels of naïve and Ag-experienced CD4 + and CD8 + T cells [34]. Although similar studies have yet to be conducted in humans, there is evidence to support an inverse correlation between serum levels of IL-7 and the severity of lymphopenia caused by conditions, such as AIDS and cytotoxic drug therapy (reviewed in Ref.…”