Downregulation of IL-17-producing T cells is associated with regulatory T cell expansion and disease progression in chronic lymphocytic leukemia

Abstract

Little is known about the immunobiology of interleukin-17 (IL-17)-producing T cells and regulatory T cells (Treg) in chronic lymphocytic leukemia (CLL). In this study, the frequencies of Th17, Tc17, and CD39(+) Treg cells were enumerated in peripheral T cells isolated from 40 CLL patients and 15 normal subjects by flow cytometry. Our results showed a lower frequency of Th17 and Tc17 cells in progressive (0.99 ± 0.12 % of total CD3(+)CD4(+) cells; 0.44 ± 0.09 % of total CD8(+) cells) compared to indolent patients (1.57 ± 0.24 %, p = 0.042; 0.82 ± 0.2 %, p = 0.09) and normal subjects (1.78 ± 0.2 %, p = 0.003; 0.71 ± 0.09 %, p = 0.04). Decrease in IL-17-producing T cells was associated with CD39(+) Treg cells expansion. Variation of IL-17-producing cells and Treg cells in indolent and progressive patients was neither associated to the expression levels of Th1- and Th2-specific transcription factors T-bet and GATA-3 nor to the frequencies of IFN-γ and IL-4-producing CD4(+) T cells in a selected number of samples. Additionally, suppressive potential of CD4(+) Treg was similar in CLL patients and normal subjects. Our data indicate that progression of CLL is associated with downregulation of IL-17-producing T cells and expansion of Treg cells, implying contribution of these subsets of T cells in the progression of CLL.

The Skewed Balance Between Tregs and Th17 in Chronic Lymphocytic Leukemia

“…Moreover, we found that reduced frequency of Th17 cells was associated with unmutated IGHV, which implied the protective role of Th17 cells in CLL. However, we observed any association between the number of IL-17 producing T cells and other prognosis markers such as CD38 or ZAP-70 expression [94]. It has recently been demonstrated that the frequency of IL-17 producing follicular Th cells was increased in CLL patients and correlated with advanced CLL stages [95].…”

“…On the other hand, cancer progression is supposed to be linked to Treg expansion and Th17 reduction [94]. The skewed balance between these cells may result in the burden of tissue inflammation, autoimmune diseases or cancer [46].…”

Ibrutinib treatment improves T cell number and function in CLL patients

“…A shift in the balance between Th1, Th2, and Th17 immune subsets in CLL patients may also be an important factor in driving disease progression, and the T cell response in CLL patients is skewed toward Th2 polarization (11). Studies in CLL patients have also shown that a decrease in IL-17-producing T cells is associated with Treg cell expansion and disease progression (12)(13)(14), while increased Th17 cell numbers correlate with improved overall survival (15). To date, success in therapeutically enhancing cell-mediated immunity in CLL has been limited.…”

“…There is accumulating evidence that a Th17 response may play a role in CLL pathogenesis. Decreased frequency of Th17 cells has been found to be associated with Treg cell expansion and disease progression in CLL patients (12)(13)(14). In contrast, elevated Th17 cells in CLL patients is associated with improved survival (15).…”

Ibrutinib enhances IL-17 response by modulating the function of bone marrow derived dendritic cells

“…27 Alternatively, in healthy individuals and patients with indolent Chronic Lymphocytic Leukemia (CLL), the frequency of IL-17 producing T cells was higher and inversely correlated with immunosuppressive T cells such as regulatory T cells (Tregs) which are found at relatively-higher frequency in progressive CLL patients. 28 This suggests that IL-17 may play a protective role in the pathogenesis of CLL. The frequency of IL-17 producing T cells was higher in mice with reduced tumor burden with primary intraocular B-cell lymphoma 29 and increased IL-17 in the tumor microenvironment was associated with improved clinical survival in patients with ovarian cancer.…”