Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation

Abstract

During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner. We analyzed changes in surface markers of peripheral blood T cells, ex vivo antigen-specific T cell responses, indoleamine 2,3-dioxygenase (IDO) activity (kynurenine/tryptophan ratio, KTR), plasma neopterin concentration, and the in vitro expression of progesterone-induced blocking factor (PIBF) in response to peripheral blood mononuclear cell culture with progesterone. We found that mid gestation is characterized by reduced antigen-specific T cell responses associated with (1) predominance of effector memory over other T cell subsets; (2) upregulation of inhibitory markers (programmed death ligand 1); (3) heightened response to progesterone (PIBF); and (4) reduced proportions of myeloid DC and concurrent IDO activity (KTR). Conversely, antigen-specific T cell responses normalized in late pregnancy and were associated with increased markers of T cell activation (CD38, neopterin). However, these changes occur with a simultaneous upregulation of immune suppressive mechanisms including apoptosis (CD95), coinhibition (TIM-3), and immune regulation (IL-10) through the course of pregnancy. Together, our data suggest that immune tolerance dominates in the second trimester and that it is gradually reversed in the third trimester in association with immune activation as the end of pregnancy approaches.

Immunobiology of Acute Chorioamnionitis

“…Large amounts of DEC-205 + DCs accumulated in both the decidua basalis and parietalis obtained from women who underwent preterm birth regardless of the presence of acute chorioamnionitis (134). Peripheral blood myeloid and plasmacytoid DCs numbers fall in the second trimester but subsequently increase in the third trimester (226,227) and become more activated (228,229). These DC populations show lower levels of costimulatory molecules CD40, CD80, and CD86 during pregnancy complications compared to healthy pregnancy (230).…”

Pregnancy Gestation Impacts on HIV-1-Specific Granzyme B Response and Central Memory CD4 T Cells

“…HIV-1 positive non-pregnant (PnP) and pregnant (PP) women were recruited from Chelsea and Westminster Hospital and St. Mary's Hospital, with any participant who delivered preterm excluded from analysis. Where possible blood was sampled at each trimester and delivery; two first trimester (<13 weeks gestation), 15 second trimester (13-27 weeks), 31 third trimester (>28 weeks) and 9 delivery samples were collected (median and range gestation were 8 (8), 22 (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), 30 (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), and 40 (37-40) respectively). Samples were processed within 6 h of collection, with peripheral blood mononuclear cells (PBMC) isolated in a containment level 3 laboratory.…”

“…Pregnancy studies of HIV-1 negative women have characterized gestational alterations in leukocyte populations and immune function; natural killer (NK) cell, dendritic cell (DC), granulocyte, monocyte, and T-cell subset counts change with gestation week in the peripheral blood, and increased CD4 T-cell effector memory (EM) populations have been observed (19,20). Furthermore, peripheral anti-viral responses alter, with in vitro Influenza A stimulation eliciting greater activation of monocyte and DC populations from pregnant women and Influenza vaccination promoting higher interferon-γ (IFNγ) production by NK and T cells ex vivo, though clinical studies show pregnancy status is associated with poorer outcomes in true Influenza infection (21,22).…”

“…Furthermore, peripheral anti-viral responses alter, with in vitro Influenza A stimulation eliciting greater activation of monocyte and DC populations from pregnant women and Influenza vaccination promoting higher interferon-γ (IFNγ) production by NK and T cells ex vivo, though clinical studies show pregnancy status is associated with poorer outcomes in true Influenza infection (21,22). However, IFNγ and IL-10 responses to Cytomegalovirus, Epstein-Barr virus and other viruses are reduced in the second trimester, suggesting pregnancy immune response modulation is virus, and potentially antigen, specific (20,23,24).…”

Pathophysiological Mechanisms of Damaging Action of Cytomegalovirus Infection in Pregnancy

“…К десятой неделе беременности «иммунологическое па-разитирование плода» сменяется развитием между ма-теринским организмом и плодом благополучного сосуществования (симбиоза), который завершается после родов. Установлено, что иммунная толерант-ность доминирует во втором триместре и что в третьем триместре она постепенно меняется в обратном на-правлении с иммунной активацией по мере приближе-ния конца беременности [54]. После оплодотворения в эндометрии развивается временная воспалительная ре-акция (повышение уровней IL-1, IL-6 и TNF-α), необхо-димая для имплантации бластоцисты [43].…”