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

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 6

The progeny of IL-15–stimulated T cells are long-lived and rapidly migrate into an extralymphoid effector site.

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The progeny of IL-15–stimulated T cells are long-lived and rapidly migra...
The 6 RMs that received a 2-dose IL-15 regimen (10 μg/kg 3 days apart) were pulsed with 30 mg/kg BrdU on the 4 days after the second IL-15 dose, and then subsequently assessed for BrdU incorporation and decay in the CD28– (CD4+ and CD8+) memory subsets in peripheral blood (A) and the overall (CD4+ and CD8+) memory populations in BAL specimens (B). These IL-15–treated RMs were compared with a cohort of 12 (A) or 16 (B) untreated RMs that were subjected to the same 4-day BrdU labeling regimen. The figure shows the mean percentage BrdU+ cells (± SEM) in the populations indicated in the IL-15–treated (filled diamonds) versus control RMs (open diamonds), with the day of the last BrdU dose designated day 0. Note that for many data points, the SEM is sufficiently small so that the error bars are obscured by the symbols. The difference in BrdU+ cell frequencies between IL-15–treated and control RMs in the blood effector memory populations was significant at P < 0.0001 and P < 0.0004 at all time points for CD4+ and CD8+ T cells, respectively. In BAL, this difference was significant at P < 0.0004 at all time points for both CD4+ and CD8+ T cells.