Increased levels of CCR7(lo)PD‑1(hi) CXCR5+ CD4+ T cells, and associated factors Bcl‑6, CXCR5, IL‑21 and IL‑6 contribute to repeated implantation failure

Abstract

In vitro fertilization-embryo transfer (IVF-ET) can be used by infertile couples to assist with reproduction; however, failure of the embryo to implant into the endometrial lining results in failure of the IVF treatment. The present study investigated the expression of chemokine receptor 7 (CCR7)(lo) programmed death-1(PD-1)(hi) chemokine receptor type 5 (CXCR5)+ cluster of differentiation 4 (CD4)+ T cells and associated factors in patients with repeated implantation failure (RIF). A total of 30 females with RIF and 30 healthy females were enrolled in the current study. Flow cytometry was used to detect the proportion of CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells in the peripheral blood. Cytokine bead arrays were performed to detect the levels of interleukin (IL)-6, −4 and −2 in the serum. ELISAs were used to detect the level of IL-21 in the serum. Quantitative real time polymerase chain reaction analysis and immunohistochemistry were used to investigate the expression of B-cell lymphoma 6 (Bcl-6), chemokine receptor type 5 (CXCR5) and IL-21 in the endometrium. The results revealed that the percentage of CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells was increased in the RIF group compared with the control group during the mid luteal phase. The mRNA and protein levels of Bcl-6, IL-21 and CXCR5 in the endometrium and the concentrations of IL-21 and IL-6 in the serum were significantly increased in the RIF group; however, no significant difference was observed between the two groups in regards to the expression of IL-4 and IL-2. Furthermore, a significant positive correlation was identified between the percentage of CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells and IL-21 and IL-6 levels. The expression of IL-21 also had a positive correlation with Bcl-6 and CXCR5 expression in the RIF group. These results suggest that increased levels of CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells and associated factors contribute to RIF and could therefore be a potential therapeutic target.

Chlorogenic acid ameliorated allergic rhinitis-related symptoms in mice by regulating Th17 cells

“…Th17 cells can cause autoimmunity and inflammation, however which can be suppressed by Th17 cells to thus attain immune homeostasis [ 12 ]. Interleukin (IL)-6 or IL-21 facilitates differentiation of CD4 + T cells into Treg cells, whereas CD4 + T differentiates into Treg cells without IL-6 or IL-21 [ 13 , 14 ]. Th17 cells are found to generate proinflammatory cytokines like IL-17, IL-22, and IL-23 to aggravate inflammation and recruit neutrophils at the site of infection [ 12 ].…”

Increased CCR7loPD-1hiC

“…According to the CCR7 and PD-1 expression on the cell surface, two major subsets were clearly identified within the circulating CXCR5 + CD4 + T cells. A study in repeated implantation failure reported the proportion of CCR7 lo PD-1 hi CXCR5 + CD4 + T cells was positively correlated with IL-21[ 31 ]. Another study found IL-21 was positively correlated with CCR7 lo PD-1 hi Tfh subset in transitional phase of Cystic echinococcosis[ 25 ].IL-21 is the main cytokine secreted by Tfh cells, reported as a critical immunomodulatory cytokine with various effects on all populations of lymphocytes.…”

Endometrial Staining of CD56 (Uterine Natural Killer), BCL-6, and CD138 (Plasma Cells) Improve Diagnosis and Clinical Pregnancy Outcomes in Unexplained Infertility and Recurrent IVF Failures: Standardization of Diagnosis with Digital Pathology

“…B-cell lymphoma 6 protein (BCL-6) was first identified as an oncogene important for proliferation in B-cell lymphomas but was later found in various tumors, as well as endometrial pathologies. Several recent studies have investigated the relationship between the expression rate of BCL-6 in the endometrial gland epithelium and endometriosis [5,[20][21][22][23]. Increased BCL-6 expression has been shown in UI and recurrent IVF failures [21,22].…”

“…Several recent studies have investigated the relationship between the expression rate of BCL-6 in the endometrial gland epithelium and endometriosis [5,[20][21][22][23]. Increased BCL-6 expression has been shown in UI and recurrent IVF failures [21,22]. BCL-6 overexpression has been associated with increased cellular proliferation [24].…”