Characterization of T follicular helper cells in allogeneic normal pregnancy and PDL1 blockage-induced abortion.

Weihong Zeng,Yi Lin,Siming Zhang,Chuanmei Qin,Yan Zhang,Fuju Tian,Jiabin Ren,Zhicui Liu,Xiaoling Ma

doi:10.1038/srep36560

Abstract

A deeper understanding of the immunological events during pregnancy will provide novel insights into the pathogenesis of pregnancy complications. The fundamental function of T follicular helper (Tfh) cells is to provide cognate help to B cells. Dysregulations of Tfh-cell function and/or development can result in various immunological diseases. However, the role and characteristics of Tfh cells during pregnancy remain unknown. Herein, an allogeneic-normal-pregnant mouse model was used, and we found that the CD4+ T cells residing at the uterus and placenta (UP) displayed a Tfh-like phenotype; and the UP-derived CD4+CXCR5hiPD-1hi and CD4+CXCR5hiICOShi Tfh cells, which showed a memory/activation phenotype, reached their peak at mid-pregnancy. These Tfh cells were located abundantly in the uterus at mid-pregnancy, but greatly increased in the placenta at late-pregnancy. Furthermore, increased foetal resorption by PDL1 blockade correlated with enhanced accumulation of Tfh cells and upregulated expressions of ICOS and PD-1 on these cells. Collectively, our findings are the first to indicate that an adequate and balanced accumulation of Tfh cells during gestation is likely to help maintaining a successful pregnancy, whereas an excessively high level of these cells could lead to abortion.

Highlights

As a novel and distinct lineage of CD4+ T cells, Tfh cells were first identified in human lymphoid tissues that express CXC chemokine receptor 5 (CXCR5) and have B cell helper function in 20009,10
We found that the levels of Tfh-associated surface molecules including CXCR5, programmed death-1 (PD-1), inducible costimulatory molecule (ICOS) and CD40 ligand (CD40L), and the memory/activation marker CD44, were remarkably higher on the CD4+ T cells derived from the uterus and placenta (UP) than those from the peripheral blood (PB) and spleen, whereas no significant differences were observed in the expressions of CTLA-4 and CD127 on CD4+ T cells between the PB and UP (Fig. 1a,b and Supplementary Fig. 1a,b)
Significantly higher levels of Tfh-associated molecules CXCR5, PD-1 and ICOS were observed on the CD4+ T cells derived from the UP compared with those from the bone marrow (BM) and thymus (Fig. 1c,d)

Summary

Introduction

As a novel and distinct lineage of CD4+ T cells, Tfh cells were first identified in human lymphoid tissues (tonsils) that express CXC chemokine receptor 5 (CXCR5) and have B cell helper function in 20009,10. An allogeneic-normal-pregnant mouse model was used to show that the CD4+ T cells residing at the uterus and placenta (UP) displayed a Tfh-like phenotype, and the UP-derived Tfh cells displaying a memory/activation phenotype were preferentially enriched at mid-pregnancy. These Tfh cells were located abundantly in the uterus at mid-pregnancy, but greatly increased in the placenta at late-pregnancy. Our findings indicated that Tfh cells might be involved in the maintenance of a successful allogeneic pregnancy

Methods

Results

Conclusion