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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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Research Article Virology Article has an altmetric score of 11

IL-15 induces CD4+ effector memory T cell production and tissue emigration in nonhuman primates

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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 1

IL-15 induces memory, but not naive, CD4+ and CD8+ T cells to proliferate.

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                  IL-15 induces memory, but not naive, CD4+
           ...
(A) The fraction of cells expressing the proliferation marker Ki-67 was determined in phenotypically defined naive versus memory, CD4+ and CD8+ T cells from the peripheral blood of 2 representative, normal RMs that were given sham injections first, followed by IL-15 injections 70 days later. (B) The change in the fraction of total CD4+ or CD8+, peripheral blood memory T cells expressing Ki-67 from baseline (defined as the average of the day –7 and day 0 values) to day 7 after the first dose is shown for all 6 RMs that were given the 2-dose IL-15 regimen. (C) The figure shows the correlated expression of CD28 and CCR7 on gated CD4+ and CD8+ memory T cells from the peripheral blood of a typical adult RM. Note that the double-negative TEM subset dominates the circulating CD8+ memory T cell population but constitutes only a very minor component of CD4+ memory T cells. CD4+ and CD8+ memory T cells in blood also differ in the presence of a significant CD28–CCR7+ subset in the latter, but not the former, population. (D) The figure shows the typical profiles of CD28 versus CCR7 expression on lung airspace and small-intestinal mucosal CD4+ and CD8+ memory T cells of an adult RM. Note that the vast majority of these memory T cells display either a CD28+CCR7– transitional or a CD28–CCR7– TEM phenotype.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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