Rebalancing TGFβ1/BMP Signals Reverse T Cell Dysfunctionality During Viral Infections And Cancer

Researchers from the Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus – USA has discovered a method to reverse T Cell Dysfunctionality that typically occurs during viral infections and cancer by rebalancing the TGFβ1/BMP signals.

The study findings were published in the peer reviewed journal: Nature Immunology.
https://www.nature.com/articles/s41590-022-01384-y

T cell dysfunctionality prevents the clearance of chronic infections and cancer. Furthermore, epigenetic programming in dysfunctional CD8⁺ T cells limits their response to immunotherapies, including immune checkpoint blockade (ICB).

However, it is unclear which upstream signals drive acquisition of dysfunctional epigenetic programs, and whether therapeutically targeting these signals can remodel terminally dysfunctional T cells to an ICB-responsive state. Here we innovate an in vitro model system of stable human T cell dysfunction and show that chronic TGFβ1 signaling in posteffector CD8⁺ T cells accelerates their terminal dysfunction through stable epigenetic changes.

Conversely, boosting bone morphogenetic protein (BMP) signaling while blocking TGFβ1 preserved effector and memory programs in chronically stimulated human CD8⁺ T cells, inducing superior responses to tumors and synergizing the ICB responses during chronic viral infection.

Thus, rebalancing TGFβ1/BMP signals provides an exciting new approach to unleash dysfunctional CD8⁺ T cells and enhance T cell immunotherapies.

Background

TGFB, also named as LAP and TGFB1, is a multifunctional peptide that controls proliferation, and cell differentiation. TGF acts synergistically with TGFA in inducing transformation process. It also acts as a negative autocrine growth factor. Dysregulation of TGFB activation and signaling may result in apoptosis. Many cells synthesize TGFB having specific receptors for it. TGFB positively and negatively regulates many other growth factors. It plays an important role in bone remodeling being a potent stimulator of an osteoblastic bone formation (PMID: 11586292).

Synonyms

CED, DPD1, LAP, TGF B1, TGF beta 1, tgf beta1, TGFB, TGFB1, TGFbeta, tgf-beta1