Circulating PD1+Vδ1+γδ T Cell Predicts Fertility in Endometrial Polyp Patients of Reproductive-Age

Abstract

Clinically, immune cell function is correlated with pathogenesis of endometrial polyp (EP) and infertility of women of reproductive-age. However, the underlying immune cell hallmark in EP patients remains unclear. Here, we focused on analyzing circulating immune cells, and attempted to reveal the correlation between peripheral immune cell functional phenotypes and fertility in EP patients. Through comparison of circulating CD4+/CD8+ T cells, NK cells, and γδ T cells between 64 EP patients and 68 healthy females, we found that γδ T cells, but not CD4+/CD8+ T cells and NK cells, were immunologically correlated with conception rate and conception interval time. Specifically, total γδ T cells and the Vδ1+PD1+ γδ T subpopulation decreased whereas the Vδ1/Vδ2 ratio increased in EP patients compared to healthy controls. Moreover, the patients with the higher Vδ1/Vδ2 ratio (median value equals 1.04) had a poorer fertility and longer interval time of conception (210 days versus 158 days for control). Meanwhile, higher Vδ1+PD1+ γδ T cell proportion (median equals 15.7) was positively correlative with both higher conception rate and shortened median conception interval time (130 days for Vδ1+PD1high group versus 194 days for Vδ1+PD1low group). Notably, in healthy controls, both Vδ1/Vδ2 ratio and Vδ1+PD1+ γδ T cell proportion correlated with pregnancy rate oppositely, comparing to EP patients. Together, our results suggested that imbalanced γδ T cell population occurred in EP patients, and that Vδ1/Vδ2 ratio and PD-1 expression of Vδ1+ γδ T cells could be potentially developed into valuable predictors for fertility in EP patients.

PD‐1 mediates decidual γδ T cells cytotoxicity during recurrent pregnancy loss

“…32 There are several studies focusing on the role of peripheral blood γδ T in predicting the failure of pregnancy. [33][34][35] In particular, the mechanisms by which decidual γδ T cells contribute to the pathogenesis of RPL are not well defined. 31 PD-1 regulates the effector function of T cells under normal physiological and pathological conditions, and maintains immune homeostasis by limiting protective immunity, [36][37][38] while PD-L1, the ligand of PD-1, is usually highly expressed on tumor cells and other hematopoietic cells 39,40 protecting target organs against autoimmune attack.…”

“…In addition, another study found that RANKL promoted the polarization of γδT cells on the decidua to Foxp3 + γδΤ cells to maintain pregnancy 32 . There are several studies focusing on the role of peripheral blood γδ T in predicting the failure of pregnancy 33‐35 . In particular, the mechanisms by which decidual γδ T cells contribute to the pathogenesis of RPL are not well defined 31 …”

Endometrial polyp is associated with a higher prevalence of chronic endometritis in infertile women

“…A history of infertility has a significantly positive connection with CE in patients with EP 21 . Inflammation‐associated cytokines (including interleukin‐6, interleukin‐17, interleukin‐1β, tumor necrosis factor‐α, and interferon‐γ) are activated by chronic inflammation resulting from CE 20–22 . EP is a lesion of local inflammation, and CE activates the inflammatory cytokines that contribute to the development of EP 20 .…”

“…20 The local inflammatory environment of the endometrium has an association with the development of recurrent EP after polypectomy. 22 We defined having at least two polyps as multiple polyps.…”

“…21 Inflammation-associated cytokines (including interleukin-6, interleukin-17, interleukin-1β, tumor necrosis factorα, and interferonγ) are activated by chronic inflammation resulting from CE. [20][21][22] EP is a lesion of local inflammation, and CE activates the inflammatory cytokines that contribute to the development of EP. 20 The local inflammatory environment of the endometrium has an association with the development of recurrent EP after polypectomy.…”