Expansion of CD4 T Lymphocytes Expressing Interleukin 17 and Tumor Necrosis Factor in Patients with Major Depressive Disorder

Miguel Angel Alvarez-Mon, Ana Maria Gómez-Lahoz, Arancha Orozco, Guillermo Lahera, David Diaz, Miguel A Ortega, Agustin Albillos, Javier Quintero, Enrique Aubá, Jorge Monserrat, Melchor Alvarez-Mon, Miguel Angel Alvarez-Mon, Ana Maria Gómez-Lahoz, Arancha Orozco, Guillermo Lahera, David Diaz, Miguel A Ortega, Agustin Albillos, Javier Quintero, Enrique Aubá, Jorge Monserrat, Melchor Alvarez-Mon

Abstract

Background: We have investigated the distribution of the Th1, Th2 and Th17 subsets in circulating CD4+ T lymphocytes and their naïve (TN), effector (TE), central (TCM) and effector memory (TEM) activation/differentiation stages in patients with major depressive disorder (MDD).

Methods: Thirty MDD patients and 30 healthy controls were studied. The counts of circulating CD4+ T lymphocytes and their distribution on the TN, TE, TCM and TEM activation/differentiation stages were analyzed by polychromatic flow cytometry. The intracytoplasmic interferon gamma (IFNγ), interleukin (IL)-4, IL-17A and tumor necrosis factor alpha (TNF-alpha) and membrane CD28 expression were also measured. The serum IFNγ, IL-4, Il-17A and TNF-alpha were measured by Luminex, respectively.

Results: MDD patients had normal counts of CD4+ T lymphocytes and of their TN, TCM and TEM subsets but increased number and percentage of TE CD4+ subset. CD4+ T lymphocytes had significantly enhanced percentage of cells that express IL-17 and TNF-alpha explained by the expansions found in the TN, TCM and, TEM and TCM, TEM and TE activation/differentiation stages, respectively. A selective increase in the percentages of TCM and TEM expressing IFNγ was also observed. We found a significant correlation between the percentages of CD4+ T lymphocytes expressing IFNγ and TNF-alpha in these patients. MDD patients showed increased serum levels of IL-17 and TNF-alpha, but normal IFNγ and IL-4 concentration.

Limitations: the cross-sectional nature of the study could be considered a limitation.

Conclusions: MDD patients have abnormal circulating CD4+ T lymphocytes with expansion of the IL-17 and TNF-alpha expressing cells as well as increased levels of circulating IL-17 and TNF-alpha.

Keywords: CD4+ T lymphocytes; clinical research; cytokines; interferon gamma; major depressive disorder; personalized medicine; precision medicine; translational research; tumor necrosis factor.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Dot plots represent the flow cytometry gating strategy and histograms of the intracellular interleukin (IL)-17A, interferon (IFN)γ, tumor necrosis factor alpha (TNF-alpha) and IL-4 expression by total circulating CD4+ T lymphocytes and TN, TCM, TEM and TE subsets in a representative case of MDD. The first row of dot plots represents the selected gates and percentages to obtain the total CD4+ T lymphocytes and TN, TCM, TEM and TE subsets in the presence of PMA (50 ng/mL) stimulation for 4 h. Histograms represent the percentages of IL-17A, IFNγ, TNF-alpha and IL-4 producing cells in the indicated CD4+ T lymphocytes subsets. Gating strategy: (A) Selection of lymphocytes by size (FSC) and complexity (SSC). (B) Exclusion of doublets. (C) Exclusion of dead cells. (D) Negative selection of CD4+ T lymphocytes using CD3+CD8- cells. (E) Expression of IFNγ and IL-17A in total CD4+ T lymphocytes. (F) Analysis of the activation/differentiation states of CD4+ T lymphocytes. (G–J) Expression of IFNγ and IL-17A in TN, TCM, TEM and TE lymphocytes.
Figure 2
Figure 2
Percentage of IL-17A, IFNγ, TNF-alpha and IL-4 expression by total circulating CD4+ T lymphocytes and TN, TCM, TEM and TE subsets in MDD patients and healthy controls after stimulation with PMA. Percentage of cells (y axis) that express the indicated cytokine by total CD4+ T lymphocytes and their TN, TCM, TEM and TE subsets (x axis) in MDD patients (black rectangles plots) and HCs (gray rectangles plots). * Significant difference between MDD and HCs for the indicated variable.
Figure 3
Figure 3
Circulating CD4+ T lymphocytes and TN, TCM, TEM and TE subsets that are able to express IL-17A, IFNγ, TNF-alpha, and IL-4 in MDD patients and HCs. Absolute number (cells/μL) (y axis that are able to express the indicated cytokine by total CD4+ T lymphocytes and their TN, TCM, TEM and TE subsets (x axis)) in MDD patients (black rectangles plots) and HCs (gray rectangles plots). * Significant difference between MDD and HCs for the indicated variable.
Figure 4
Figure 4
Correlations between the percentages of IFNγ and TNF-alpha expression by CD4+ T lymphocytes in MDD patients. Pearson correlation coefficient between percentages of expression of IFNγ and TNF-alpha was 0.562 (p < 0.0001).
Figure 5
Figure 5
Circulating serum levels of IL-17A, IFNγ, TNF-alpha and IL-4 in MDD patients (black rectangles plots) and HCs (gray rectangles plots). Serum concentrations (pg/μL) (y axis) of IFNγ, IL-17A, IL-4 and TNF-alpha. * Significant difference between MDD and HCs for the indicated variable.

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