: The objective of this application is to study the connection between thymic-selection of a biased T-cell receptor (TCR) repertoire [due to expression of biased diversity of the complexes of peptides with Major Histocompatibility Complex (MHC) proteins] and organ-specific autoimmunity. Limitation of the MHC-peptide repertoire leads to diminished negative selection and gives a selective advantage to T-cells expressing receptors that have loose requirements for interactions with a specific peptide. Such receptors rely on other interactions (with MHC itself and especially with co-receptors) to achieve the level of signaling sufficient to allow T-cells to survive. If T-cells with such TCRs have autoreactive potential, they may be the cause of organ-specific autoimmunity after their egress from the thymus. We hypothesize that any strong bias of the repertoire of peptides bound to MHC molecules leads to imbalance in positive and negative selection allowing potentially autoreactive TCRs to slip through negative selection and trigger autoimmunity in the periphery. MM14.4 TCR transgenic animals have been made using TCR derived from a mouse with a restricted MHC-peptide repertoire. These mice develop severe autoimmunity in the forms of psoriasoform dermatitis (closely resembling human psoriasis) or lymphoid tissue-associated proliferative disease. The following specific aims will be pursued: I. Determine the mechanisms of selection of autoreactive T-cells produced in mice with a biased MHC-peptide repertoire. The role of MHC and co-receptors in selection of T-cells with autoreactive potential in mice with a constrained MHC-peptide repertoire will be studied. The frequency of selection of similar cells by biased peptide repertoire will be estimated. II. Elucidate the mechanisms of organ-specific autoimmune diseases caused by aberrant T-cell selection. General characterization of the autoimmunity in MM14.4 mice, the cellular components responsible for disease initiation and progression, and target cells and antigens will be studied. The significance of the proposed research program is that it links together the expression of biased MEC-peptide repertoire, selection of altered T-cell repertoire, and resultant autoimmunity.
| Logunova, Nadezda N; Viret, Christophe; Pobezinsky, Leonid A et al. (2005) Restricted MHC-peptide repertoire predisposes to autoimmunity. J Exp Med 202:73-84 |
