New research by scientists at the University of California, San Diego (UCSD) demonstrates through a previously undescribed form of cell auto-signaling, T cells were shown to activate themselves in peripheral tissues, fueling their ability to attack tumors.
The findings are described in Immunity in an article titled, “cis-B7:CD28 interactions at invaginated synaptic membranes provide CD28 co-stimulation and promote CD8+ T cell function and anti-tumor immunity,” and may lead to new anti-tumor therapeutics.
“B7 ligands (CD80 and CD86), expressed by professional antigen-presenting cells (APCs), activate the main co-stimulatory receptor CD28 on T cells in trans,” wrote the researchers. “However, in peripheral tissues, APCs expressing B7 ligands are relatively scarce. This raises the question of whether and how CD28 co-stimulation occurs in peripheral tissues. Here, we report that CD8+ T cells displayed B7 ligands that interacted with CD28 in cis at membrane invaginations of the immunological synapse as a result of membrane remodeling driven by phosphoinositide-3-kinase (PI3K) and sorting-nexin-9 (SNX9).”
A key part of the T cell process in protecting against infection and against cancer is the binding of B7, a protein on the surface of antigen-presenting cells, with CD28, a receptor on T cells. This B7:CD28 interaction is a major driver of the T-cell immune response.
Recent research has revealed that T cells can actually produce their own B7 or take the B7 protein from the antigen-presenting cells and bring it along with them, but exactly why they do this has remained unclear.
In the current study, the researchers found that T cells could indeed self-activate by puckering their cell membrane inwards to allow the B7 protein and the CD28 receptor to bind each other.
“People often assume the cell membrane is flat, but it actually looks more like a coastline with lots of coves and bays,” said co-senior author Enfu Hui, PhD, professor in the School of Biological Sciences at UCSD. “We found that local membrane curvatures are actually a rich dimension of T cell auto-signaling, which is paradigm-shifting in a field that assumed this only happened across cells.”
The researchers then confirmed that this auto-stimulation was effective in boosting T-cell function and slowing tumor growth in a mouse model of cancer.
“When a T cell exits a lymph organ and enters a tumor environment, it’s like leaving home and going for a long trek in the woods,” said Hui. “The same way a hiker brings snacks to sustain them through the trip, the T cells bring their own signal to keep them going. Now the exciting question is, how much farther will they go if we can provide more food?”
“We’ve found a way that T cells are able to live outside of their normal homes and survive in the foreign environment of a tumor, and we can now develop clinical strategies for increasing or decreasing these pathways to treat disease,” said Hui.