T-cell Receptor and Autoimmune Disease

The investigators constructed a mouse model of spontaneous autoimmune thyroid disease (AITD, Hashimoto thyroiditis) by generation of transgenic mice expressing a portion of an autoreactive T-cell receptor (TCR) that specifically recognized an amino acid sequence of human thyroid peroxidase (hTPO) (TPO_535-551) obtained from the thyroid gland of a patient with AITD. They did it by ligating the gene sequence encoding the extracellular domain of the human TCR to the gene sequence encoding the intracellular domain of the mouse TCR. Within the sequence TPO_535-551 are 2 overlapping epitopes with distinctly different biologic properties: TPO_536-547, an agonistic stimulatory epitope, and TPO_537-548, an antagonistic epitope that can induce anergy in vitro. TPO_536-547 is a "cryptic" epitope displayed in an inflamed thyroid gland. The human/mouse chimeric TCR was inserted into the genome of a mouse in which the gene encoding V(D)J recombinase had been inactivated (Rag1^-/-, Recombination-activating gene 1); Rag1^-/- animals are not able to synthesize antibodies or TCRs of the adaptive immune system (OMIM 179615). Initially, the investigators demonstrated that the hybrid human/mouse TCR was expressed on peripheral CD4⁺T and CD8⁺T cells which proliferated in response to TPO_536-547. They also demonstrated that comparable mouse and human TPO amino acid sequences were functionally similar. TCR⁺-Rag1^-/- mice developed hypothyroidism spontaneously between 12-20 weeks of age. Their thyroid glands revealed histological changes of thyroiditis with infiltration by mononuclear cells, follicular destruction, and apoptosis of thyroid epithelial cells (Figure). The authors concluded that TCRs directed to epitopes of TPO alone could induce thyroid inflammation.

Frame1

The TAZ10 transgenic mouse model and the immunological basis for Hashimoto thyroiditis. (a) Thyroid follicle and the location of the major thyroid autoantigens: thyroid peroxidase (TPO), thyroglobulin (Tg) and the thyroid-stimulating hormone receptor (TSHR). (b) Immunological mechanisms leading to the spectrum of human autoimmunity with differing pathological and clinical characteristics. Graves hyperthyroidism is caused directly by TSHR autoantibodies that activate the TSHR. Hypothyroidism in Hashimoto thyroiditis is associated with autoantibodies to TPO (and less commonly to Tg), but the relative contributions to thyrocyte damage by autoantibodies, TPO-specific T cells and/or cytokines is unknown. The TAZ10 model of Quaratino et al. shows that TPO-specific T cells are sufficient to induce the histopathological and clinical features of Hashimoto disease. However, how CD8⁺ T cells and cytokines secreted by CD4⁺ T cells contribute to destruction has yet to be determined. T3, triiodothyronine. (Michael Pace)

Editor’s Comment: These investigators demonstrated that TCRs specific for an epitope of TPO (TPO_535-551) were able to produce AITD in intact mice in the absence of mature B cells and autoantibodies to TPO. The mechanisms by which the transgenic TCR detected the cryptic epitope of mouse TPO and the thyroid epithelia were destroyed were not identified. It is interesting to speculate that the conceptual model utilized in these experiments might be applicable to other autoimmune diseases and to the possible design of therapeutic interventions targeted to a specific TCR. In an accompanying editorial, McLachlan and Rapoport¹ suggest that expansion of the population of TCRs directed toward epitopes of TPO (eg, TPO_536-547) that enhance anergy might be able to prevent thyroid inflammation and destruction.


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Current GGH - Vol. 24 No. 1 View table of contents Download PDF
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