Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells
Masahiro Hirakawa, Tiago R. Matos, Hongye Liu, John Koreth, Haesook T. Kim, Nicole E. Paul, Kazuyuki Murase, Jennifer Whangbo, Ana C. Alho, Sarah Nikiforow, Corey Cutler, Vincent T. Ho, Philippe Armand, Edwin P. Alyea, Joseph H. Antin, Bruce R. Blazar, Joao F. Lacerda, Robert J. Soiffer, Jerome Ritz
Masahiro Hirakawa, Tiago R. Matos, Hongye Liu, John Koreth, Haesook T. Kim, Nicole E. Paul, Kazuyuki Murase, Jennifer Whangbo, Ana C. Alho, Sarah Nikiforow, Corey Cutler, Vincent T. Ho, Philippe Armand, Edwin P. Alyea, Joseph H. Antin, Bruce R. Blazar, Joao F. Lacerda, Robert J. Soiffer, Jerome Ritz
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Clinical Research and Public Health Immunology

Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells

Abstract

CD4+ regulatory T cells (CD4Tregs) play a critical role in the maintenance of immune tolerance and prevention of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. IL-2 supports the proliferation and survival of CD4Tregs and previous studies have demonstrated that IL-2 induces selective expansion of CD4Tregs and improves clinical manifestations of chronic GVHD. However, mechanisms for selective activation of CD4Tregs and the effects of low-dose IL-2 on other immune cells are not well understood. Using mass cytometry, we demonstrate that low concentrations of IL-2 selectively induce STAT5 phosphorylation in Helios+ CD4Tregs and CD56brightCD16– NK cells in vitro. Preferential activation and expansion of Helios+ CD4Tregs and CD56brightCD16– NK cells was also demonstrated in patients with chronic GVHD receiving low-dose IL-2. With prolonged IL-2 treatment for 48 weeks, phenotypic changes were also observed in Helios– CD4Tregs. The effects of low-dose IL-2 therapy on conventional CD4+ T cells and CD8+ T cells were limited to increased expression of PD-1 on effector memory T cells. These studies reveal the selective effects of low-dose IL-2 therapy on Helios+ CD4Tregs and CD56bright NK cells that constitutively express high-affinity IL-2 receptors as well as the indirect effects of prolonged exposure to low concentrations of IL-2 in vivo.

Authors

Masahiro Hirakawa, Tiago R. Matos, Hongye Liu, John Koreth, Haesook T. Kim, Nicole E. Paul, Kazuyuki Murase, Jennifer Whangbo, Ana C. Alho, Sarah Nikiforow, Corey Cutler, Vincent T. Ho, Philippe Armand, Edwin P. Alyea, Joseph H. Antin, Bruce R. Blazar, Joao F. Lacerda, Robert J. Soiffer, Jerome Ritz

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Figure 5

Proportional representation of each lymphocyte subset during low-dose IL-2 therapy in vivo.

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Proportional representation of each lymphocyte subset during low-dose IL...
(A) Contour viSNE plots of CD4+ T cells in a representative patient with chronic graft-versus-host disease (GVHD) receiving low-dose IL-2 therapy. The far-left color map identifies CD4+ T cell subsets based on expression of CD25 and FoxP3, and the map is colored to identify conventional CD4+ T cells (CD4Tcons) and CD4+ Tregs (CD4Tregs). The contour maps represent cell density in each region of the map at the indicated time point (in weeks [W]) during IL-2 therapy. (B) Summary of CD4+ T cell subset distributions in 14 patients with chronic GVHD receiving low-dose IL-2 therapy, expressed as percentages of total CD4+ T cells, at the indicated time point during therapy. (C) Contour viSNE plots of Tregs in a representative patient at the indicated time points during IL-2 therapy. The far-left color map identifies CD4Treg subpopulations that were defined in Figure 1B, and the color for each subpopulation is indicated. (D) Summary of CD4Treg subsets in 14 patients receiving daily IL-2 expressed as a percentage of total CD4Tregs (left), naive CD4Tregs (middle), and memory CD4Tregs (right) at the indicated times during therapy. (E) Contour viSNE plots of NK cells in a representative patient receiving daily IL-2. The far-left color map next to the contour plots identifies NK subsets that were defined in Figure 1E, and the color for each NK subset is indicated. (F) Summary of changes in NK cell subsets in 14 patients receiving daily IL-2 expressed as a percentage of total CD56+ NK cells. Median values and interquartile ranges for each data point in each of these graphs are provided in Supplemental Table 3. Statistical comparisons with pretreatment values are also provided in Supplemental Table 3. Pre, before IL-2 therapy; Post, 4 weeks after stopping IL-2 therapy.