Activated CLL cells regulate IL-17F–producing Th17 cells in miR155-dependent and outcome-specific manners
Byeongho Jung, Gerardo Ferrer, Pui Yan Chiu, Rukhsana Aslam, Anita Ng, Florencia Palacios, Michael Wysota, Martina Cardillo, Jonathan E. Kolitz, Steven L. Allen, Jacqueline C. Barrientos, Kanti R. Rai, Nicholas Chiorazzi, Barbara Sherry
Byeongho Jung, Gerardo Ferrer, Pui Yan Chiu, Rukhsana Aslam, Anita Ng, Florencia Palacios, Michael Wysota, Martina Cardillo, Jonathan E. Kolitz, Steven L. Allen, Jacqueline C. Barrientos, Kanti R. Rai, Nicholas Chiorazzi, Barbara Sherry
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Research Article Hematology Immunology

Activated CLL cells regulate IL-17F–producing Th17 cells in miR155-dependent and outcome-specific manners

Abstract

Chronic lymphocytic leukemia (CLL) results from expansion of a CD5+ B cell clone that requires interactions with other cell types, including T cells. Moreover, patients with CLL have elevated levels of circulating IL-17A+ and IL-17F+ CD4+ T (Th17) cells, with higher numbers of IL-17A+ Th17 cells correlating with better outcomes. We report that CLL Th17 cells expressed more miR155, a Th17-differentiation regulator, than control Th17 cells, despite naive CD4+ T (Tn) cell basal miR155 levels being similar in both. We also found that CLL cells directly regulated miR155 levels in Tn cells, thereby affecting Th17 differentiation, by documenting that coculturing Tn cells with resting or activated (Bact) CLL cells altered the magnitude and direction of T cell miR155 levels; CLL Bact cells promoted IL-17A+ and IL-17F+ T cell generation by an miR155-dependent mechanism, confirmed by miR155 inhibition; coculture of Tn cells with CLL Bact cells led to a linear correlation between the degree and direction of T cell miR155 expression changes and production of IL-17F but not IL-17A; and Bact cell–mediated changes in Tn cell miR155 expression correlated with outcome, irrespective of IGHV mutation status, a strong prognostic indicator. These results identify a potentially unrecognized CLL Bact cell–dependent mechanism, upregulation of Tn cell miR155 expression and subsequent enhancement of IL-17F+ Th17 generation, that favors better clinical courses.

Authors

Byeongho Jung, Gerardo Ferrer, Pui Yan Chiu, Rukhsana Aslam, Anita Ng, Florencia Palacios, Michael Wysota, Martina Cardillo, Jonathan E. Kolitz, Steven L. Allen, Jacqueline C. Barrientos, Kanti R. Rai, Nicholas Chiorazzi, Barbara Sherry

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Figure 3

Effect of CLL B cells on differentiation of Tn cells to Th17A and Th17F cells.

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Effect of CLL B cells on differentiation of Tn cells to Th17A and Th17F ...
(A) Design and timeline of coculture. B cells were prestimulated or not, as in Figure 2 (days –3 to 0), and then cocultured with Tn cells for 3 days (days 0 to +3). At this point, the combined cell populations were stimulated with anti–CD3 and anti–CD28–coated beads for an additional 7 days (total of 10 days; days +3 to +10). ELISAs were conducted for IL-17A, IL-17F, and IFN-γ using culture supernatants collected on the days indicated. Data from analyses of supernatants and cells collected on day 10 are plotted in panels B–G. (B–D) Scatter plots with bars indicating the concentration (pg/mL) of secreted IL-17A (B), IL-17F (C), and IFN-γ (D) as determined by ELISA. (E–G) Scatter plots with bars indicating percentages of CD4+IL-17A+ cells (E), CD4+IL-17F+ cells (F), and CD4+IFN‑γ+cells (G), as determined by flow cytometry. *P < 0.05, **P < <0.01, *P < 0.001 by Friedman 1-way repeated-measure ANOVA by ranks followed by Dunn’s multiple comparisons test. IC, intracellular.