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Optimal T-Cell Receptor Affinity for Inducing Autoimmunity

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Optimal T-Cell Receptor Affinity for Inducing Autoimmunity Optimal T-cell receptor affinity for inducing autoimmunity Sabrina Koehlia, Dieter Naehera, Virginie Galati-Fourniera, Dietmar Zehnb,c, and Ed Palmera,1 aDepartments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, CH-4031 Basel, Switzerland; bSwiss Vaccine Research Institute, CH-1066 Epalinges, Switzerland; and cDivision of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland Edited* by Philippa Marrack, Howard Hughes Medical Institute, National Jewish Health, Denver, CO, and approved October 14, 2014 (received for review February 17, 2014) T-cell receptor affinity for self-antigen has an important role in them to differentiate into short-lived effector T cells (20). Below- establishing self-tolerance. Three transgenic mouse strains express- threshold T cells expand less efficiently but can still threaten the ing antigens of variable affinity for the OVA transgenic-I T-cell host upon recognition of below-threshold antigen in an in- receptor were generated to address how TCR affinity affects the fectious environment (21). In fact, below-threshold T cells are efficiency of negative selection, the ability to prime an autoimmune indeed able to mediate autoimmunity after immunization with response, and the elimination of the relevant target cell. Mice recombinant Listeria monocytogenes (Lm) expressing a below- expressing antigens with an affinity just above the negative threshold antigen (22). selection threshold exhibited the highest risk of developing ex- Antigen affinity affects important parameters related to the perimental autoimmune diabetes. The data demonstrate that development of autoimmunity: (i) the efficiency of central toler- close to the affinity threshold for negative selection, sufficient ance, (ii) the efficiency of T-cell priming, and (iii) the efficiency of numbers of self-reactive T cells escape deletion and create an destroying a target cell expressing the self-antigen. In this study, we increased risk for the development of autoimmunity. examined these parameters individually and in combination. We show a striking threshold effect on central deletion, T-cell priming, Tcell| TCR | affinity | tolerance | autoimmunity and cytolysis of antigen-expressing cells in the target tissue. These experiments demonstrate that T cells expressing TCRs just above protective and self-tolerant T-cell repertoire is generated in the affinity threshold have the highest potential to induce an Athe thymus (1–3), where negative selection reduces the autoimmune disease. number of self-reactive thymocytes with autoimmune potential (4– Results 6). However, negative selection is not a perfect process, and a small β number of self-reactive T cells are found in the periphery (7). RIP-Variant Mice Express Variant OVA Proteins in Pancreatic Cells. Previous work from our laboratory defined the affinity threshold In RIP-OVA mice, the transgenic RIP drives OVA expression in β where negative selection is initiated (1, 8). Thymocytes expressing pancreatic Langerhans islet cells, proximal tubular epithelial MHC I restricted T-cell receptors (TCRs) undergoing negative cells in the kidney, mTECs in the thymus, and testes of male mice. For these studies, two different RIP-OVA lines were used: RIP- selection when binding a self-antigen with a Kd ≤ 6 μM and positive selection when binding a self-antigen with lower affinity (8, 9). sOVA and RIP-mOVA express the soluble and membrane forms The autoimmune regulator transcription factor ensures that of ovalbumin, respectively. We also generated three new strains tissue-restricted antigens are also expressed in the thymus within of RIP-variant transgenic mice expressing the mOVA variants: resident medullary thymic epithelial cells (mTECs) (10); how- Q4H7 (RIP-mQ4H7, below-threshold), T4 (RIP-mT4, thresh- ever, individual self-antigens are expressed on only a small per- old), and Q4R7 (RIP-mQ4R7, above-threshold). To determine whether OVA-variant antigens are expressed in pancreatic β cells, centage of mTECs, and the presentation of a single antigen is OT-I mice were crossed to the various RIP-OVA–variant mice to limited on the mTEC or dendritic cell surface (11–14). There- fore, self-reactive T cells might stochastically escape negative selection (15). A high frequency of self-reactive T cells in the Significance peripheral repertoire correlates with the susceptibility to develop autoimmune disease. Studies showed that mice with high fre- The adaptive immune system has the potential to generate a quencies of myelin-specific T cells are more susceptible for the self-reactive response, which can eventually lead to an auto- induction of experimental autoimmune encephalomyelitis com- immune disease. To avoid this outcome, T lymphocytes with pared with mice with lower frequencies of these cells (16). In high-affinity, self-reactive antigen receptors are blocked from single transgenic mice expressing lymphocytic choriomeningitis vi- entering the mature T-cell pool (negative selection). Given this rus (LCMV) glycoprotein (gp33) or nucleoprotein with a polyclonal mechanism for removing dangerous high-affinity T cells, we T-cell repertoire, cytotoxic T lymphocytes (CTLs) generated during wondered whether autoimmunity is more likely to be caused by the immune response are of lower affinity compared with non- chronic stimulation of low-affinity T cells or by stimulation of transgenic mice, suggesting that the highest affinity T cells for the a few high-affinity T cells that escaped negative selection. In this neoantigen were removed from the T-cell repertoire by central paper, we show that T cells with an affinity just above the se- lection threshold can bypass negative selection and have the tolerance (16–18). Nevertheless, the remaining lower affinity T cells highest potential to cause an experimental autoimmune disease. were capable of inducing diabetes upon LCMV infection. Similar – findings have been reported for the rat insulin promoter (RIP) Author contributions: S.K., D.N., V.G.-F., and E.P. designed research; S.K., D.N., and V.G.-F. membrane-bound form of ovalbumin (mOVA) mouse line coex- performed research; D.N. and D.Z. contributed new reagents/analytic tools; S.K. and E.P. pressing the OT-I TCR (OVA transgenic-I T-cell receptor) β-chain analyzed data; and S.K. and E.P. wrote the paper. (17). Self-reactive T cells also play a role in the spontaneous de- The authors declare no conflict of interest. velopment of diabetes in nonobese diabetic (NOD) mice (19). *This Direct Submission article had a prearranged editor. Recently, we reported a peripheral correlate of the thymic 1To whom correspondence should be addressed. Email: [email protected]. negative selection affinity threshold such that above-threshold This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ligands drive T cells into asymmetrical T-cell division, allowing 1073/pnas.1402724111/-/DCSupplemental. 17248–17253 | PNAS | December 2, 2014 | vol. 111 | no. 48 www.pnas.org/cgi/doi/10.1073/pnas.1402724111 Downloaded by guest on September 29, 2021 generate double-transgenic F1 animals (i.e., OT-I TCR × RIP- OVA F1, OT-I TCR × RIP-mQ4H7 F1, OT-I TCR × RIP-mT4 F1, and OT-I TCR × RIP-mQ4R7 F1). Surprisingly, double- transgenic F1 mice of all crosses showed high mortality within the first 2 wk after birth (89% in OT-I × RIP-mQ4H7, 100% in OT-I × RIP-mT4, 97% in OT-I × RIP-mQ4R7, 72% in OT-I × RIP-mOVA, and 52% in OT-I × RIP-sOVA) (Fig. 1). Blood glu- cose levels of newborn mice were elevated in all crosses, indicating severe hyperglycemia. From these results, we conclude that all RIP- OVA–variant transgenic mice expressed the OVA protein in the β cells of the corresponding RIP-OVA strains and that central tolerance mechanisms were overwhelmed in these F1 mice. Below-Threshold T Cells Comprise a Low Risk of Autoimmunity. We wondered how target cell antigen affinity influences the de- velopment of diabetes following infection with a pathogen ex- pressing a high-affinity epitope (i.e., molecular mimicry). Accordingly, we transferred OT-I T cells into RIP-variant mice, which were sub- sequently infected with Lm expressing the highest affinity OVA epitope (Lm-OVA). RIP-transgenic mice expressing threshold (RIP- mT4) and above-threshold (RIP-mQ4R7, RIP-OVA) OVA variants developed diabetes when as few as 3 × 103 OT-I T cells were transferred (Fig. 2A). The transgenic strain RIP-mQ4H7 expressing the below-threshold variant Q4H7 did not develop diabetes; adop- × 5 tive transfer of as many as 3 10 OT-I T cells did not result Fig. 2. Below-threshold T cells comprise a low risk for autoimmunity. (A) in glucosuria. Urine glucose was monitored in RIP-OVA– and RIP-OVA–variant mice injec- Autoimmune diseases can also be initiated by priming auto- ted with the indicated number of OT-I T cells, followed by infection with Lm- reactive T cells with self-antigens that are identical to the target OVA. (B) Immunization with self-antigen expressed in Lm. Mice injected with antigen. Therefore, OT-I T cells were transferred into various RIP- the indicated number of OT-I T cells were infected with Lm expressing the transgenic strains, followed by immunization with Lm expressing same self-antigen 1 d later. Mice were considered diabetic if urine glucose levels were sustained at >1,000 mg/dL for >2 d. The asterisk indicates pooled the same OVA variant as is expressed in the host pancreas (Fig. results of RIP-sOVA (100%, n = 2–5 mice per group) and RIP-mOVA (100%, 2B). Because diabetes induction was similar in RIP-sOVA and n = 2–5 mice per group). RIP-mOVA mice, we combined them into one group (RIP-OVA). A breakdown of the two strains is provided in the legend for Fig. 2. We observed efficient diabetes induction with only 3 × 103 trans- when the immunizing and target antigens are identical, only above- ferred OT-I T cells in mice expressing above-threshold self-anti- threshold antigens efficiently induce autoimmune diabetes.
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