Sp1 links CD46 to CD4 T cell metabolic fitness, survival, and retroviral control.

Authors

Parul Singh, Luopin Wang, Pavitra Ramdas, Shyaman M Jayasundara, Gaelle Le Friec, Natalia Kunz, Prakriti Mudvari, Erin E West, Ayden Case, Nicolas S Merle, Jack A Bibby, Henrik Hasle, Eli A Boritz, Majid Kazemian, Claudia Kemper

Published in

Science immunology. Volume 11. Issue 121. Pages eaeb5857. Jul 10, 2026. Epub Jul 10, 2026.

Abstract

CD46, a human-specific complement receptor, regulates gene programs essential for T helper 1 (T_H1) cell differentiation, yet how it exerts direct transcriptional control remains unclear. We show that the CD46 signaling domain cytoplasmic tail 1 (CYT-1) engages the transcription factor Sp1 in human CD4 T cells to dynamically modulate Sp1-DNA interactions. Beyond promoting T_H1 cell induction, CD46-Sp1-controlled programs support naive CD4 T cell survival by maintaining nutrient transporter expression and suppressing the intrinsic caspase 9-caspase 3 apoptotic pathway. The CD46-Sp1 axis also restrains HIV transcription in infected CD4 T cells in vitro. Disruption of CYT-1-Sp1-regulated programs identifies T cells from individuals with HIV who exhibit incomplete viral suppression during antiretroviral therapy. Together, these findings define a human-specific transcriptional mechanism linking complement signaling to metabolic adaptation, apoptosis regulation, and antiviral defense, highlighting an unexpected role for CD46 in coordinating T cell homeostasis and host protection.

PMID:
42430443
Bibliographic data and abstract were imported from PubMed on 11 Jul 2026.

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