cTfh Cell Activation and Changes in BTLA and LAG‐3 Expression Differentially Associate With Poor Pregnancy Outcome in Plasmodium falciparum Placental Malaria

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Continuous exposure to antigens drives the activation of circulating T follicular helper (cTfh) cells, promoting high‐affinity antibody production. However, sustained stimulation may impair their function through the upregulation of immunoregulatory markers like B and T lymphocyte attenuator (BTLA) and Lymphocyte-activation gene 3 (LAG-3) . This study investigated the role of cTfh cells and their subsets in Plasmodium falciparum ‐associated placental malaria (PM). In a cross‐sectional study conducted in Yaounde, Cameroon (March 2022–May 2023), peripheral, placental, and cord blood samples were collected from 49 women at delivery. Hemoglobin (Hb) levels were recorded, and peripheral blood mononuclear cells (PBMCs), intervillous blood mononuclear cell (IVBMCs), and cord blood mononuclear cells (CBMCs) were isolated for multiparametric flow cytometry analysis of cTfh cells and subsets (ICOS − and ICOS + cTfh subsets). PM was associated with increased cTfh cell frequencies in both PBMC and IVBMC. PM‐negative (PM−) women displayed higher ICOS − cTfh cell frequencies, while PM‐positive (PM+) women had elevated ICOS + cTfh cells that correlated with parasitemia levels. BTLA expression was downregulated in bulk cTfh and ICOS − cTfh cells during PM. Interestingly, cTfh frequencies in IVBMC positively correlated with baby weight, while cTfh frequencies in PBMC and IVBMC negatively associated with maternal Hb. Furthermore, BTLA and LAG‐3 expression in IVBMC negatively correlated with birth weight. Together, these findings highlight altered cTfh cell profiles during PM, influencing maternal and neonatal outcomes.

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