The CD4 T cell-intrinsic C3-like molecule CD109 prevents hyper-inflammatory T cell responses

Immune cell autonomous complement expression and function emerges as pivotal regulator of tissue immunity and T cell biology. Specifically, CD4 T cell intrinsic engagement of CD46 by TCR stimulation-triggered generation of the CD46 ligand C3b, is required for IFN-γ production. In consequence, CD46-deficient patients are unable to generate normal Th1 responses. We identified CD109, a GPI anchored C3-like protein and a direct CD46 signaling induced target. Despite its known ability to regulate TGF-ßR1 signaling in cancer cells, a direct functional activity for CD109 on T cells remains unexplored. 

Human CD4 T cells lacking CD109 expression displayed significantly augmented IFN-γ and IL-17 production upon in vitro stimulation under non-skewing conditions. Similarly, CD4 T cells from Cd109^–/– mice showed in vitro Th1 and Th17 hyperactivation and caused more severe EAE pathology in vivo. Unexpectedly, T cell CD109 does not control TGF-ß signaling but restrains IFN-γ and/or IL-17 by binding to and inhibiting the activity of a non-canonical costimulatory molecule linked to Th1/Th17 biology. Guided by modeling and Cryo-EM data, we designed a CD109/costimulatory inhibitory peptide that recapitulates the phenotype observed in CD109-deficient T cells. 

Together, these data suggest that the C3-like protein CD109 serves as an important molecular brake (or switch) on CD4 T cells by fine-tuning costimulatory signals upstream of the hyper-inflammatory Th1/Th17 induction pathways.