IL-7 Administration Alters the CD4:CD8 Ratio, Increases T Cell Numbers, and Increases T Cell Function in the Absence of Activation

Abstract

IL-7 is vital for the development of the immune system and profoundly enhances the function of mature T cells. Chronic administration of IL-7 to mice markedly increases T cell numbers, especially CD8+ T cells, and enhances T cell functional potential. However, the mechanism by which these effects occur remains unclear. This report demonstrates that only 2 days of IL-7 treatment is needed for maximal enhancement of T cell function, as measured by proliferation, with a 6- to 12-fold increase in the proportion of CD4+ and CD8+ T cells in cell cycle by 18 h of ex vivo stimulation. Moreover, a 2-day administration of IL-7 in vivo increases basal proliferation by 4- and 14-fold in CD4+ and CD8+ T cells, respectively. These effects occur in the absence of cytokine production, increases in most activation markers, and changes in memory markers. This enhanced basal proliferation is the basis for the increase in T cell numbers in that IL-7 induces an additional 60% and 85% of resting CD4+ and CD8+ T cells, respectively, to enter cell cycle in mice given IL-7 for 7 days. These results demonstrate that in vivo administration of IL-7 increases T cell numbers and functional potential via a homeostatic, nonactivating process. These findings may suggest a unique clinical niche for IL-7 in that IL-7 therapy may increase T cell numbers and enhance responses to specific antigenic targets while avoiding a general, nonspecific activation of the T cell population.

IL‐7Rα expression on CD4+ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

“…More recently it has been established that a disruption of T cell homeostasis through the persistent stimulation of naïve cells, pushing them along the path of differentiation, is a contributing factor to HIV disease progression [2, 8,9]. Under normal conditions, when there is a reduction of T cell numbers in the periphery, levels of IL-7 increase to send survival signals via the IL-7R to promote antigen independent, or homeostatic proliferation to rebalance T cell numbers [16,44]. In lymphopenic HIV-infected individuals, there is an elevated level of IL-7 caused by the homeostatic response to T cell depletion [45,46].…”

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.…”

Innate Immune Cell CD45 Regulates Lymphopenia-Induced T Cell Proliferation

“…This may affect naive T cell survival and contribute to a lower level of LIP observed in 45RAGKO mice. IL-7 is known to alter the CD4:CD8 T cell ratio, with the addition of exogenous IL-7 being shown to selectively expand CD8 T cells even in the absence of T cell depletion (41). This implies that CD8 T cells are more responsive to IL-7 than CD4 T cells, which correlates with the defect we observed in 45RAGKO mice where low IL-7 levels are present and the LIP of CD8 T cells is more severely affected than that of CD4 T cells.…”