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.
View: Text | PDF
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

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

×

Figure 3

CD28– , CCR7– TEM cells are poorly responsive to IL-2.

Options: View larger image (or click on image) Download as PowerPoint
CD28– , CCR7– TEM...
(A) The CD4+ and CD8+ memory T cell subsets defined by CD28 and CCR7 expression in the peripheral blood in 2 representative RMs (of 4 total) were assessed for expression of Ki-67 before, during, and after 2 weeks of twice-weekly administration of IL-2. Note that IL-2 preferentially induced proliferation in the CD28+CCR7– component of both the CD4+ and the CD8+ memory populations. (B) The mean (± SEM) change in percentage Ki-67 from baseline (the average of day –7 and day 0 values) to peak response (day 7 or 10 after the first cytokine dose) is shown for the CD28/CCR7–defined peripheral blood memory T cell subsets in all 4 IL-2–treated RMs, and the 4 RMs that received at least 3 doses of IL-15 (the pre-peak doses on days 0, 3, and 7, matching the pre-peak IL-2 dosing schedule). While IL-2 demonstrated a superior (to CD4+) or similar (to CD8+) ability to induce proliferation among CD28+CCR7– transitional memory T cells, IL-15 was dramatically better than IL-2 in initiating proliferation within both the CD4+ and the CD8+, CD28–CCR7– TEM subsets. *0.05 < P < 0.005; **P < 0.005.