We will study the mechanisms of human T cell hypersensitivity to beryllium (Be2+) and nickel (Ni2+) metal ions at the structural level, and confirm these mechanisms in human subjects. While evidence suggests that these metal ions are presented to pathologic T cells by an MHC molecule pre-complexed with a self-peptide, little is known about how the metal ions bind MHC, how the metal/MHC complexes are recognized by T cells, and how these processes are modulated in humans. Chronic beryllium disease (CBD) is a debilitating lung disease principally caused by workplace exposure to airborne Be2+. The disease is highly associated with MHCII alleles, particularly HLA-DP2 (DP2), that have a Glu at amino acid 69 in the chain helix. Our collaborators found that in human lungs, the T cell response to Be2+ is dominated by those bearing V5.1 with various T cell receptor (TCR) a chains, all recognizing an identical DP2/peptide/ Be2+ complex. Working with the AV22 TCR, we found that the very small Be2+ cation is buried deep in a flexible P5-P7 pocket, and influences TCR binding indirectly via local changes in the DP2-peptide surface conformation. With the goal of determining whether this mechanism is generalizable to other TCR-MHC interactions, we will test whether this flexible presentation of Be2+ applies to recognition by AV22 of Be2+/DP2 with other self- peptides, and to TCRs unrelated to AV22. Ni2+ is the most common cause of contact dermatitis, affecting 10-15% of the human population, and is also involved in reactions to metal implants such as knee and hip replacements. Here, too, specific TCR V motifs interact with a limited array of MHCs. In the skin, we have shown that V17 T cells such as the Ani2.3 T cell clone recognize Ni2+ bound to an HLA-DR52c (DR52c)-self peptide complex. Our data strongly suggest that the large Ni2+ cation is surface exposed in this complex, forming a major contact area for the TCR. Ni2+ appears to be bound to the same area of MHCII that is engaged by Be2+, i.e. in the space between the bound peptide and the MHCII chain. We will test this idea with structural studies on various Ni2+ specific TCRs bound to MHCII/peptide/Ni2+,and confirm the presence of Ni2+ reactive TCRs found in the blood of patients with failing metal implants due to nickel sensitization. We will pursue the following aims Aim 1 To elucidate the mechanism of presentation of HLA-DP2/ Be2+ to T cells, we will determine if Be2+ will influence engagement of the V5.1 TCR, AV22, indirectly via conformational changes in the DP2- self peptide surface, and determine how DP2/peptide/Be2+ is recognized by a TCR that is structurally not related to AV22, the V3.1 bearing TCR, RP11.
Aim 2 To elucidate the mechanisms of presentation of MHCII/Ni2+ to T cells, we will define and characterize Ni2+ dependent peptides for the V17 TCR ANi2.3, determine whether Ni2+ is bound to DR1 in the same way as to DR52c, and whether the DR1/peptide/Ni2+/ SE9 (another V17 TCR) interaction is similar to that of DR52c/peptide/Ni2+/ANi2.3, and analyze the Ni2+ specific T cells in the blood of patients with joint implant failure due to nickel sensitization. Understanding the role of metal ions in these interactions will shed light on the mechanisms of metal induced immune diseases, and may help in the development of compounds that can modulate such interactions.
Although metal hypersensitivities are common immune diseases, little is known about how metal ions are recognized by human T cells and thus trigger several serious medical conditions. We aim to determine the structural requirements for T cell activation by metal ions and antigen presenting cells. The results will further our understanding of the mechanisms of metal induced hypersensitivity and autoimmune diseases and will provide the structures based upon which we may be able to design therapeutic compounds to prevent or treat these diseases.
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| Zhang, Yan; Wang, Yang; Anderson, Kirsten et al. (2017) Using DR52c/Ni2+ mimotope tetramers to detect Ni2+ reactive CD4+ T cells in patients with joint replacement failure. Toxicol Appl Pharmacol 331:69-75 |
| Fontenot, Andrew P; Falta, Michael T; Kappler, John W et al. (2016) Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation. J Immunol 196:22-7 |
| Jin, Niyun; Wang, Yang; Crawford, Frances et al. (2015) N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes. Proc Natl Acad Sci U S A 112:13318-23 |
