Biology subjects

Soliman, C.

Publications and source records attributed to Soliman, C..

3 recordsLinked to original sources

bioRxiv2026

Conserved T cell receptor usage underpins recognition of CD1c presenting a mycobacterial lipid

The mechanism by which T cell receptors (TCR) recognise mycobacterial lipids presented by CD1 family members not well understood. We used CD1c tetramers loaded with the mycobacterial phosphomycoketide (PM) or mannosyl-PM (MPM) to isolate T cells ex vivo in healthy blood donors and in individuals from a tuberculosis (TB)-endemic region of South Africa, with higher frequencies observed in individuals from the TB-endemic region. High throughput analysis of >200 paired CD1c-mycoketide tetramer+ {beta}TCRs identified a conserved TCR motif, encoded by TRBV4-1 or TRBV7-9 variable region genes in greater than half of TCRs sequenced. A cryo-EM structure of a TRBV7-9+ TCR in complex with CD1c-PM demonstrated that the TCR bound to the F side of CD1c, directly contacting the phospholipid antigen and F-portal residues. Analysis of multiple T cell clones interacting with CD1c mutants suggested that this TCR docking mode is representative of the larger TRBV7-9+ T cell population. Collectively, this study provides insight into mycobacterial lipid-antigen recognition by CD1c-restricted T cells. SummaryCao and Soliman et al study CD1c-restricted human T cells that recognize mycobacterial phosphomycoketide lipids, where they are shown to be more frequent in blood a TB-endemic region. The authors describe a strong TCR-{beta} repertoire bias and use cryoEM to provide a high-resolution structure of an archetypal TCR engaging CD1c in complex with a mycobacterial lipid.

immunology↗

bioRxiv2026

Specific targeting of MR1-antigen complexes using nanobodies

T cell receptor mimic (TCRm) antibodies and nanobodies that specifically bind peptide-HLA complexes have great therapeutic potential, as they can target polymorphic HLA on tumour cells furnishing peptides derived from tumour-associated antigens. MR1 is an MHC class-I-like molecule that exhibits limited polymorphism that binds and presents conserved metabolites, such as 5-OP-RU, derived from microbial riboflavin biosynthesis. Whether antibodies targeting such MR1-5-OP-RU complexes can be generated remains unclear. Using yeast display technology and in vitro affinity maturation, a nanobody with high affinity and fine specificity toward MR1-5-OP-RU complex was generated. These nanobodies bind both mouse and human MR1-5-OP-RU and inhibited MAIT cell responses to 5-OP-RU in vitro and in vivo demonstrating therapeutic potential. Moreover, we provide a molecular basis underpinning the fine specificity of these nanobodies, solving the crystal structures of MR1 in complex with either 5-OP-RU or Ac-6-FP. Here, the nanobody co-bound MR1 and 5-OP-RU, akin to a TCRm antibody. Moreover, we engineer bispecific antibodies targeting both MR1-5-OP-RU and CD3, that drive broad T cell killing of bacterially-infected cells as well as tumour cells treated with 5-OP-RU, thereby providing proof-of-principle for targeting the MR1 molecule with with TCRm-based nanobodies. One Sentence SummaryWe report the development of a nanobody targeting MR1-5-OP-RU complex and demonstrate its utility to modulate MAIT cells responses, and as a bispecific engager.

immunology↗

bioRxiv2023

Vgamma9Vdelta2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

Butyrophilin (BTN) molecules are emerging as key regulators of T cell immunity, however, how they trigger cell-mediated responses is poorly understood. Here, the crystal structure of a gamma-delta T cell receptor ({gamma}{delta}TCR) in complex with BTN member 2A1 (BTN2A1) revealed that BTN2A1 engages the side of the {gamma}{delta}TCR, leaving the apical TCR surface bioavailable. We reveal that BTN3A1 is a second {gamma}{delta}TCR ligand, that co-engages {gamma}{delta}TCR via binding to this accessible apical surface. BTN2A1 and BTN3A1 also directly interact with each other in cis, and structural analysis revealed formation of W-shaped heteromeric multimers. This BTN2A1-BTN3A1 interaction involved the same epitopes that BTN2A1 and BTN3A1 each use to engage {gamma}{delta}TCR; indeed, either forced separation or locking together of BTN2A1 and BTN3A1 resulted in enhanced or abrogated {gamma}{delta}TCR interaction, respectively. Our findings reveal a new paradigm in immune activation, whereby {gamma}{delta}TCRs recognize dual epitopes on BTN2A1 and BTN3A1 complexes.

immunology↗