Research Projects

We have two projects available that seek to establish the role and underlying mechanisms of conventional and unconventional T cells, including MAIT and CD1-restricted T cells, in allergies to drugs, including antibiotics. 

These projects involve joint supervision by Dr Sidonia Eckle and Dr Catarina Almeida from the Godfrey lab, drawing on expertise in MAIT cells and CD1-restricted T cells, respectively, as well as in conventional T cells.

Rationale: Drugs represent life-saving therapies. However, drugs can also cause unwanted immune-mediated adverse drug reactions, also referred to as hypersensitivities. Manifestations can range from rashes, to severe, life-threatening anaphylaxis. There are no known predictors for these immune-mediated reactions, and the only viable solution is to discontinue treatment in patients that present such manifestations, ruling out first-line treatments for serious illnesses. Thus, drug hypersensitivities remain a fundamentally unsolved global clinical problem with high economic burden.

Many small molecule drug-hypersensitivities are presumed to be T cell-mediated and various mechanisms as to how conventional T cells restricted by MHC-I molecules were proposed over 20 years ago by Pichler et al. [1], despite very little experimental evidence. To date, only one study elucidated the molecular mechanism of a T cell-mediated small molecule-drug hypersensitivity and this was not accounted for by those initially proposed by Pichler et al.: the anti-HIV drug abacavir binds to HLA-B*57:01 together with an altered repertoire of self-peptides and induces conventional T cell responses upon T cell receptor (TCR) recognition, associated with the abacavir-hypersensitivity-syndrome [2]. Whereas most studies into T cell-mediated hypersensitivities have focused on conventional T cells restricted by polymorphic MHC-I/-II molecules presenting peptide antigens, there are families of unconventional T cells, which instead are restricted by monomorphic MHC-I-like molecules presenting non-peptide antigens. They include natural killer T (NKT) cells which recognise lipids presented by CD1d, and Mucosal-Associated Invariant T (MAIT) cells which recognise small molecule metabolites presented by MR1. Their role in hypersensitivities remains unexplored [3], but is supported by our strong preliminary data, including published studies revealing drug-like small molecules binding to CD1d or MR1 [4, 5]. 

Objectives and approaches. Hypothesis: Small-molecule drugs interact with antigen presenting MHC-I/-II or MHC-I-like molecules, leading to conventional or unconventional T cell activation and thereby hypersensitivities.
Aim (i): Investigate if candidate drugs activate T cells from patients with drug hypersensitivities and determine which T cells are involved and the type of T cell response, using in vitro cellular assays and flow cytometry. 
Aim (ii): Investigate if the T cell-mediated drug response depends on antigen presenting molecules and determine which one is involved (MHC-I, MHC-II, CD1a, CD1b, CD1c, CD1d or MR1) using cellular assays as per Aim (i) but with blocking antibodies for each molecule.
Aim (iii): Investigate the TCR role, specificity, and biases in the T cell-mediated drug reactivity by isolating single responding T cells using fluorescence activated cell sorting (FACS) and sequencing their TCR genes. TCR reporter cell lines will then be generated by retroviral transduction of cell lines with TCR genes to formally demonstrate TCR dependency and specificity in cellular assays using flow cytometry. 
Aim (iv): Determine the molecular basis as to how drugs mediate T cell recognition using X-ray crystallography with the help of collaborators.

References. [1] Pichler W, Yawalkar N, Schmid S, Helbling A. Pathogenesis of drug-induced exanthems. Allergy. 2002;57:884-93.
[2] Illing PT, Vivian JP, Dudek NL, Kostenko L, Chen Z, Bharadwaj M, Miles JJ, Kjer-Nielsen L, Gras S, Williamson NA, Burrows SR, Purcell AW, Rossjohn J, McCluskey J. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature. 2012;486:554-8.
[3] de Lima Moreira M, Souter MNT, Chen Z, Loh L, McCluskey J, Pellicci DG, Eckle SBG. Hypersensitivities following allergen antigen recognition by unconventional T cells. Allergy. 2020.
[4] Almeida CF, Smith DGM, Cheng TY, Harpur CM, Batleska E, Nguyen-Robertson CV, Nguyen T, Thelemann T, Reddiex SJJ, Li S, Eckle SBG, Van Rhijn I, Rossjohn J, Uldrich AP, Moody DB, Williams SJ, Pellicci DG, Godfrey DI. Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d. Proc Natl Acad Sci U S A. 2021;118.
[5] Keller AN, Eckle SB, Xu W, Liu L, Hughes VA, Mak JY, Meehan BS, Pediongco T, Birkinshaw RW, Chen Z, Wang H, D'Souza C, Kjer-Nielsen L, Gherardin NA, Godfrey DI, Kostenko L, Corbett AJ, Purcell AW, Fairlie DP, McCluskey J, Rossjohn J. Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells. Nat Immunol. 2017;18:402-11.

Contact project supervisor for further
information and application enquiries