Yunlong Zhao Lab

Immune cells, like T cells, communicate through dedicated co-receptor signaling pathways. Historically speaking, these signaling pathways were thought to primarily take place through trans-interactions – communication between cells via ligands and receptors on different cell membranes. However, our studies reveal the significance of cis-interactions – cell-intrinsic communication between receptors and ligands on the same cell membrane. These two dimensions of signaling—cis and trans—are not isolated events but tightly interwoven, creating a spatially regulated network that controls T-cell activity.

We aim to understand the spatial orchestration of these interactions. How do T cells integrate signals across the membrane landscape? How does the positioning of receptors and ligands in two-dimensional space dictate T cell function? By decoding this spatial regulation, our goal is to translate these findings into therapeutic strategies, ultimately improving patient outcomes. 

The T-cell response is tightly regulated by immune checkpoints, such as CTLA-4 and PD-1. CTLA-4 is constitutively expressed on regulatory T cells and downregulates immune responses when bound to CD80 and CD86 ligands, while PD-1 interaction with PD-L1 suppresses the killing of tumor cells by T cells. 

Our research discovered that PD-L1 interacts with CD80 in cis and, further, that cis-PD-L1:CD80 interactions can rewire trans-signaling pathways by inhibiting the binding of PD-L1 with PD-1 and CD80 with CTLA-4, while maintaining the ability of CD80 to interact with another of its cognate stimulatory receptors, CD28. Therefore, cis-PD-L1:CD80 interactions modulate the balance between inhibition (PD-1 and CTLA-4) and stimulation (CD28). This finding opens new possibilities for therapies that shift immune responses from suppression to activation, leading to more effective cancer treatments. 

CD28 is a co-stimulatory T-cell receptor that responds to binding CD80 and CD86 (B7 ligands). However, even though these ligands are not abundantly expressed in peripheral tissues, CD28 co-stimulation of T cells in peripheral tissues still occurs. Our laboratory provided evidence that through cis-interactions, B7 ligands on CD8+ T cells engage CD28 at membrane invaginations of the immunological synapse, resulting in a self-sustaining co-stimulatory mechanism. This finding points to cis signaling as an important modulator of T-cell functionality. 

Dr. Zhao received his PhD in cell signaling in host-pathogen interactions from the Institute of Microbiology, Chinese Academy of Sciences in Beijing. He then completed his postdoctoral fellowship at the University of California, San Diego, where he focused on T-cell signaling. Dr. Zhao joined St. Jude as an Assistant Member in the Department of Immunology and is a key contributor to the Center of Excellence in Pediatric Immuno-Oncology. His research focuses on T-cell co-receptor signaling, specifically the influence of spatial regulation on T cell anti-tumor responses.