Eric S. Huseby
Autoimmunity and the Development of T Cell Tolerance of Self
The major interest of my lab is to decipher how T cells develop tolerance to self proteins and the autoimmune consequences of when tolerance fails. The major route of establishing immunological tolerance of self occurs during the development of T cells in the thymus. If the T cell receptor (TCR) on developing T cells (thymocytes) binds MHC + self peptides in the thymus with high affinity, the thymocyte is signaled to die. However, if the TCR on the thymocyte binds MHC + self peptides within a range of medium affinity, T cells are signaled to live and enter the mature T cell repertoire.
Most mature T cells, when activated, are pro-inflammatory in nature. However, other T cells adopt an anti-inflammatory phenotype and function to turn off immune responses. The signaling events which instruct whether thymocytes live or die and whether mature T cells are pro-inflammatory or anti-inflammatory originate from how the TCR binds MHC + self peptides during development in the thymus. To identify how the biophysics of TCR binding MHC + peptides instructs thymocytes, we have measured the binding affinity and kinetics of binding for a series of TCRs binding several MHC + peptide combinations. Using these TCR - MHC + peptide combinations, we are studying how different biophysical parameters influence the development T cells.
Although thymic deletion purges most T cells with reactivity for self proteins, autoimmune diseases clearly demonstrate that T cell tolerance of self is incomplete. Many studies have indicated that everyone harbors T cells reactive to self proteins, however only a fraction of people succumb to autoimmune disease. Thus not all self reactive T cell repertoires are pathogenic. Using a T cell mediated model of the autoimmune disease multiple sclerosis, we are determining whether there is a T cell intrinsic difference in self-reactive, pathogenic versus non-pathogenic T cell repertoires or whether all self reactive T cell repertoires have the capability to pathogenic and autoimmunity is predominately a reaction to a specific triggering event.