Receptor Deformation Model May Solve T-cell Triggering Puzzle
T-cells, an essential component of the immune system, are activated after the T-cell's antigen receptor (TCR) binds to an antigen presenting cell's peptide-loaded major histocompatibility complex (pMHC). How this activation occurs has puzzled immunologists for more than two decades. However, it is considered critical to understanding how the immune system works.
Terri Finkel, M.D., Ph.D., and Zhengyu (Mark) Ma, M.D., Ph.D., Division of Rheumatology, have developed a model that shows how an activating signal from the TCR is initiated, or triggered, by the engagement of pMHC. This model, the "receptor deformation model," is an entirely new explanation for how TCR triggering occurs. After being published in PLoS Biology, it was featured in Science and a "Hypothesis" paper in The FASEB Journal.
Dr. Finkel and colleagues looked at an aspect of the triggering process that had been previously overlooked — the mechanical stress exerted on pMHC-TCR interaction by cytoskeletal forces where the dynamic T cell and the antigen-presenting cell meet.
Building on the knowledge that T cells respond well to antigens on antigen presenting cells but do not respond to the same antigens in solution, the team used an artificial system comprised of a lipid bilayer or plastic surface to present defined foreign pMHCs to the TCR. They found that T cells are triggered by very low numbers (less than 10) of pMHCs, even in the absence of endogenous (self) pMHCs or the surface molecules of antigen presenting cells.
TCR triggering critically depended on the T-cell adhesion to a surface and a functioning cytoskeleton that gives T cells the ability to move. These findings led to the receptor deformation model, in which the TCR signal is initiated by conformational changes of the TCR complex, induced by a pulling force. This is the first model to take into consideration the role of external mechanical forces in pMHC-TCR binding in a dynamic 2D environment.
This new model addresses all three aspects — mechanism, sensitivity and specificity — of the TCR triggering puzzle. "By introducing mechanical force into the equation, the receptor deformation model offers a straightforward mechanism for T-cell antigen receptor signal initiation, and explains the extraordinary sensitivity and specificity of the T-cell immune response" says Dr. Ma.
This finding may lead to further understanding of a key step in the recognition of foreign antigens by the immune system, as well as the identification of potential targets for the manipulation of T-cell activation and self-tolerance by drugs.
The study was supported by the NIH, Children's Hospital, the Joseph L. Hollander Chair and the Stokes Institute.
Future studies, funded by a new 2-year NIH grant, will study single molecules of TCR and pMHC to focus on the external force required to detach interacting T-cells and antigen presenting cells and the components of the cytoskeleton critically involved in the process.