Self-Tolerance and the Composition of T Cell Repertoire

Abstract

T cell recognition of self-major histocompatibility complex-peptide complexes dictates the composition of the T cell receptor repertoire. Research projects in our laboratory deal with the mechanisms that regulate the composition of the repertoire specific for self-antigens and the defects that can result in autoimmunity. Two different types of disease models are under investigation: juvenile (type I) diabetes and cancer. Both of these diseases are impacted by the presence of anti-self CD8 cells, yet in opposite ways. By understanding the mechanisms of peripheral tolerance and the reasons they fail in autoimmunity, we may learn how to prevent undesirable autoimmunity and how to encourage an autoimmune response when it is needed to eliminate tumor cells.

CD8+ cytotoxic T lymphocytes isolated from allogeneic healthy donors recognize HLA class Ia/Ib–associated renal carcinoma antigens with ubiquitous or restricted tissue expression

“…Indeed, several reports demonstrated tumor-induced anergy or tolerance of autologous antitumor CTLs in RCC as well as other cancer types. 37,38 Successful generation of RCC-reactive CD8 ϩ T lymphocytes has also been achieved using PBMCs of allogeneic healthy donors who had only a single HLA class I allele match with their RCC stimulator cell lines. 34,39 However, such an experimental set-up promotes dominant anti-HLA mismatch T-cell responses in vitro, potentially masking or even hindering the development of self-HLA-restricted antitumor CTLs.…”

In Defense against Pathogens. Both Plant Sentinels and Foot Soldiers Need to Know the Enemy,

“…Failure of animal defenses to exhibit proper self-recognition or sequestration leads to various forms of autoimmune dysfunctions and serious collateral damage (Sherman et al, 2000;Medzhitov and Janeway, 2002). Only in a few studies has the specific nonself toxicity of plant-encoded antimicrobial proteins/peptides been examined.…”

Highly diverged MHC class I mismatches are acceptable for haematopoietic stem cell transplantation

“…In generating a T-cell repertoire with a sufficiently narrow responsiveness for self-MHC, positive thymic selection limits the capacity to recognize MHC molecules the structure and sequence of which have diverged extensively. [14][15][16][17][18] Many X5a5b mismatched MHC class I molecules fall into this category of extensively diverged MHC molecules. If no T-cell alloreactivity against a X5a5b mismatch can be measured in vitro, we expect that transplantation across a X5a5b mismatch will not lead to T-cell alloreactivity after transplantation in vivo.…”