IL-15 induces CD4+ effector memory T cell production and tissue emigration in nonhuman primates
Louis J. Picker, … , Michael K. Axthelm, Francois Villinger
Louis J. Picker, … , Michael K. Axthelm, Francois Villinger
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1514-1524. https://doi.org/10.1172/JCI27564.
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IL-15 induces CD4+ effector memory T cell production and tissue emigration in nonhuman primates

Abstract

HIV infection selectively targets CD4+ effector memory T (TEM) cells, resulting in dramatic depletion of CD4+ T cells in mucosal effector sites in early infection. Regeneration of the TEM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4+ and CD8+ TEM cells with little effect on the naive or central memory T (TCM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. TEM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2′-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4+ TEM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4+ T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets.

Authors

Louis J. Picker, Edward F. Reed-Inderbitzin, Shoko I. Hagen, John B. Edgar, Scott G. Hansen, Alfred Legasse, Shannon Planer, Michael Piatak, Jeffrey D. Lifson, Vernon C. Maino, Michael K. Axthelm, Francois Villinger

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Figure 2

IL-15 selectively acts on TEM and transitional memory T cells.

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IL-15 selectively acts on TEM and t...
(A) The CD4+ and CD8+ memory T cell subsets defined by CD28 and CCR7 expression (see Figure 1C) in peripheral blood were assessed for expression of Ki-67 before, during, and after IL-15 treatment (arrows). Note that CD4+ memory cells lack a significant CD28–CCR7+ component, accounting for why only 3 populations are shown for this lineage. (B) The change in percentage Ki-67+ from baseline (the average of day –7 and day 0 values) to peak (either day 7 or day 10) is shown for the designated CD4+ (black) and CD8+ (red) memory subsets in 4 different RMs that received at least 3 doses of IL-15 (10 μg/kg) on days 0, 3, and 7. The IL-15–induced changes in percentage Ki-67 for each of the 3 comparable CD4+ versus CD8+ memory subsets (means provided in the figure) were not significantly different. (C) The figure shows the expression of CCR5 by the CD4+ memory subsets defined by CD28 and CCR7 in the peripheral blood of a representative adult RM. (D) The fraction of CCR5+, CD4+ peripheral blood memory T cells expressing Ki-67 is shown before, during, and after IL-15 treatment (arrows; 10 μg/kg) in the same 2 representative RMs depicted in A. As would be expected based on the staining pattern shown in C, IL-15 induced a substantial increase in proliferation within the CCR5-expressing, CD4+ memory population.