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IL-17/IL-10 double-producing T cells: new link between infections, immunosuppression and acute myeloid leukemia.

Musuraca G, De Matteis S, Napolitano R, Papayannidis C, Guadagnuolo V, Fabbri F, Cangini D, Ceccolini M, Giannini MB, Lucchesi A, Ronconi S, Mariotti P, Savini P, Tani M, Fattori PP, Guidoboni M, Martinelli G, Zoli W, Amadori D, Carloni S - J Transl Med (2015)

Bottom Line: A strong increase of Th17 cells producing immunosuppressive IL-10 was observed in AML patients compared with healthy donors.In addition, stimulation of AML-derived T cells with a Candida albicans antigen induced significantly lower IFN-γ production than that observed in healthy donors; intriguingly, depletion of patient Th17 cells restored IFN-γ production after stimulation.Th17 cells could thus represent a new target to improve AML immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. gerardo.musuraca@irst.emr.it.

ABSTRACT

Background: Acute myeloid leukemia (AML) is an incurable disease with fatal infections or relapse being the main causes of death in most cases. In particular, the severe infections occurring in these patients before or during any treatment suggest an intrinsic alteration of the immune system. In this respect, IL-17-producing T helper (Th17) besides playing a key role in regulating inflammatory response, tumor growth and autoimmune diseases, have been shown to protect against bacterial and fungal pathogens. However, the role of Th17 cells in AML has not yet been clarified.

Methods: T cell frequencies were assessed by flow cytometry in the peripheral blood of 30 newly diagnosed AML patients and 30 age-matched healthy volunteers. Cytokine production was determined before and after culture of T cells with either Candida Albicans or AML blasts. Statistical analyses were carried out using the paired and unpaired two-tailed Student's t tests and confirmed with the non parametric Wilcoxon signed-rank test.

Results: A strong increase of Th17 cells producing immunosuppressive IL-10 was observed in AML patients compared with healthy donors. In addition, stimulation of AML-derived T cells with a Candida albicans antigen induced significantly lower IFN-γ production than that observed in healthy donors; intriguingly, depletion of patient Th17 cells restored IFN-γ production after stimulation. To address the role of AML blasts in inducing Th17 alterations, CD4+ cells from healthy donors were co-cultured with CD33+ blasts: data obtained showed that AML blasts induce in healthy donors levels of IL-10-producing Th17 cells similar to those observed in patients.

Conclusions: In AML patients altered Th17 cells actively cause an immunosuppressive state that may promote infections and probably tumor escape. Th17 cells could thus represent a new target to improve AML immunotherapy.

No MeSH data available.


Related in: MedlinePlus

Alterations in T helper cells from HV and untreated AML patients. a Representative dot plots of cytokine production by CD4+ cells isolated from a HV before and after in vitro priming with IL-6 and then with phorbol 12-myristate 13-acetate (PMA) and ionomycin (I). b Representative dot plots of CD4+ cells from an AML patient before and after stimulation with IL-6 and PMA + I. c Pooled data obtained after stimulation from 30 HV (white circles) and 30 AML patients (black circles) and mean values (bars). d Gating strategy used to identify the CD4+ CD25highFoxP3+ cells. e Mean and standard deviation of Treg frequency from HV and AML patients.
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Fig1: Alterations in T helper cells from HV and untreated AML patients. a Representative dot plots of cytokine production by CD4+ cells isolated from a HV before and after in vitro priming with IL-6 and then with phorbol 12-myristate 13-acetate (PMA) and ionomycin (I). b Representative dot plots of CD4+ cells from an AML patient before and after stimulation with IL-6 and PMA + I. c Pooled data obtained after stimulation from 30 HV (white circles) and 30 AML patients (black circles) and mean values (bars). d Gating strategy used to identify the CD4+ CD25highFoxP3+ cells. e Mean and standard deviation of Treg frequency from HV and AML patients.

Mentions: As shown in Figure 1a, b, flow cytometric analysis revealed that the frequencies of T helper populations were altered in AML patients in comparison to healthy donors. In particular, Th1 and Th2 percentages were lower in patients (4.0 ± 2.1 and 0.8 ± 0.6% respectively) than in controls (12.8 ± 4.3 and 2.9 ± 1.8% respectively), whereas Th17 cells showed a 1.5-fold increase in AML patients compared to HV (P = 0.013) (Figure 1c). All the observed differences were statistically significant.Figure 1


IL-17/IL-10 double-producing T cells: new link between infections, immunosuppression and acute myeloid leukemia.

Musuraca G, De Matteis S, Napolitano R, Papayannidis C, Guadagnuolo V, Fabbri F, Cangini D, Ceccolini M, Giannini MB, Lucchesi A, Ronconi S, Mariotti P, Savini P, Tani M, Fattori PP, Guidoboni M, Martinelli G, Zoli W, Amadori D, Carloni S - J Transl Med (2015)

Alterations in T helper cells from HV and untreated AML patients. a Representative dot plots of cytokine production by CD4+ cells isolated from a HV before and after in vitro priming with IL-6 and then with phorbol 12-myristate 13-acetate (PMA) and ionomycin (I). b Representative dot plots of CD4+ cells from an AML patient before and after stimulation with IL-6 and PMA + I. c Pooled data obtained after stimulation from 30 HV (white circles) and 30 AML patients (black circles) and mean values (bars). d Gating strategy used to identify the CD4+ CD25highFoxP3+ cells. e Mean and standard deviation of Treg frequency from HV and AML patients.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4502949&req=5

Fig1: Alterations in T helper cells from HV and untreated AML patients. a Representative dot plots of cytokine production by CD4+ cells isolated from a HV before and after in vitro priming with IL-6 and then with phorbol 12-myristate 13-acetate (PMA) and ionomycin (I). b Representative dot plots of CD4+ cells from an AML patient before and after stimulation with IL-6 and PMA + I. c Pooled data obtained after stimulation from 30 HV (white circles) and 30 AML patients (black circles) and mean values (bars). d Gating strategy used to identify the CD4+ CD25highFoxP3+ cells. e Mean and standard deviation of Treg frequency from HV and AML patients.
Mentions: As shown in Figure 1a, b, flow cytometric analysis revealed that the frequencies of T helper populations were altered in AML patients in comparison to healthy donors. In particular, Th1 and Th2 percentages were lower in patients (4.0 ± 2.1 and 0.8 ± 0.6% respectively) than in controls (12.8 ± 4.3 and 2.9 ± 1.8% respectively), whereas Th17 cells showed a 1.5-fold increase in AML patients compared to HV (P = 0.013) (Figure 1c). All the observed differences were statistically significant.Figure 1

Bottom Line: A strong increase of Th17 cells producing immunosuppressive IL-10 was observed in AML patients compared with healthy donors.In addition, stimulation of AML-derived T cells with a Candida albicans antigen induced significantly lower IFN-γ production than that observed in healthy donors; intriguingly, depletion of patient Th17 cells restored IFN-γ production after stimulation.Th17 cells could thus represent a new target to improve AML immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. gerardo.musuraca@irst.emr.it.

ABSTRACT

Background: Acute myeloid leukemia (AML) is an incurable disease with fatal infections or relapse being the main causes of death in most cases. In particular, the severe infections occurring in these patients before or during any treatment suggest an intrinsic alteration of the immune system. In this respect, IL-17-producing T helper (Th17) besides playing a key role in regulating inflammatory response, tumor growth and autoimmune diseases, have been shown to protect against bacterial and fungal pathogens. However, the role of Th17 cells in AML has not yet been clarified.

Methods: T cell frequencies were assessed by flow cytometry in the peripheral blood of 30 newly diagnosed AML patients and 30 age-matched healthy volunteers. Cytokine production was determined before and after culture of T cells with either Candida Albicans or AML blasts. Statistical analyses were carried out using the paired and unpaired two-tailed Student's t tests and confirmed with the non parametric Wilcoxon signed-rank test.

Results: A strong increase of Th17 cells producing immunosuppressive IL-10 was observed in AML patients compared with healthy donors. In addition, stimulation of AML-derived T cells with a Candida albicans antigen induced significantly lower IFN-γ production than that observed in healthy donors; intriguingly, depletion of patient Th17 cells restored IFN-γ production after stimulation. To address the role of AML blasts in inducing Th17 alterations, CD4+ cells from healthy donors were co-cultured with CD33+ blasts: data obtained showed that AML blasts induce in healthy donors levels of IL-10-producing Th17 cells similar to those observed in patients.

Conclusions: In AML patients altered Th17 cells actively cause an immunosuppressive state that may promote infections and probably tumor escape. Th17 cells could thus represent a new target to improve AML immunotherapy.

No MeSH data available.


Related in: MedlinePlus