CD46, a human-specific complement receptor, regulates gene programs essential for T helper 1 (TH1) 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 TH1 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.
Systemic complement protects the vascular compartment, while cell-intrinsic complement components shape tissue immunity by regulating normal cell physiology and metabolism. In human CD4 T helper cells, intracellular C5a generation engages the intracellular receptor C5aR1, promoting Th1 differentiation. Here, we identify a counter-regulatory role for the alternative C5a receptor, C5aR2, in restraining T cell effector responses by studying the first reported family with a heterozygous C5aR2 mutation. The affected individuals present with an autoinflammatory syndrome, and disease penetrance tracks with the mutation: the affected mother and child carry the variant, whereas the unaffected father and siblings do not.
To define the impact of the C5aR2 mutation, we performed single-cell RNA sequencing, in vitro stimulation assays, and flow cytometric profiling of patient and control PBMCs. CPM inhibition or deletion, C5aR2 agonism, and transcriptional profiling of Cpm- or C5ar2-deficient mouse CD4 T cells, along with a T cell transfer colitis model, were used to define mechanistic consequences.
Patient samples exhibited a profound loss of naïve and central memory CD4 and CD8 T cells, accompanied by expansion of IFN-γ—producing effector memory populations. The C5aR2 mutation abolishes C5aR2 β-arrestin signaling. Additionally, we identified carboxypeptidase M (CPM) as a T cell—intrinsic enzyme generating C5a-desArg, a potent ligand for C5aR2. Loss or inhibition of CPM heightened inflammatory T cell responses, which were normalized by C5aR2 agonism. Mouse Cpm- or C5ar2-deficient CD4 T cells displayed overlapping transcriptional perturbations, and Cpm-knockout CD4 T cells induced more severe colitis.
Collectively, our data uncover a previously unrecognized CPM-dependent mechanism that balances C5aR1 and C5aR2 signaling to limit pathological T cell activation, revealing an intrinsic complement-driven checkpoint that constrains effector T cell immunity.
NHLBI/NIH intramural program
Immune Mechanisms of Human Disease (HUM)
Erin E. West, Nicolas S. Merle, Ayden Case et al.· Journal of Immunology· 0 citations
