MHC-related protein 1-restricted recognition of cancer via a semi-invariant TCR-α chain

Garry Dolton; Hannah Thomas; Li Rong Tan; Cristina Rius Rafael; Stephanie Doetsch; Giulia Andreea Ionescu; Lucia F. Cardo; Michael D. Crowther; Enas Behiry; Théo Morin; Marine E. Caillaud; Devinder Srai; Lucia Parolini; Md Samiul Hasan; Anna Fuller; Katie Topley; Aaron Wall; Jade R. Hopkins; Nader Omidvar; Caroline Alvares; Joanna Zabkiewicz; John Frater; Barbara Szomolay; Andrew K. Sewell

doi:10.1172/JCI181895

MHC-related protein 1-restricted recognition of cancer via a semi-invariant TCR-α chain

Garry Dolton, Hannah Thomas, Li Rong Tan, Cristina Rius Rafael, Stephanie Doetsch, Giulia Andreea Ionescu, Lucia F. Cardo, Michael D. Crowther, Enas Behiry, Théo Morin, Marine E. Caillaud, Devinder Srai, Lucia Parolini, Md Samiul Hasan, Anna Fuller, Katie Topley, Aaron Wall, Jade R. Hopkins, Nader Omidvar, Caroline AlvaresJoanna Zabkiewicz, John Frater, Barbara Szomolay, Andrew K. Sewell^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

The T cell antigen presentation platform MR1 consists of 6 allomorphs in humans that differ by no more than 5 amino acids. The principal function of this highly conserved molecule involves presenting microbial metabolites to the abundant mucosalassociated invariant T (MAIT) cell subset. Recent developments suggest that the role of MR1 extends to presenting antigens from cancer cells, a function dependent on the K43 residue in the MR1 antigen binding cleft. Here, we successfully cultured cancer-activated, MR1-restricted T cells from multiple donors and confirmed that they recognized a wide range of cancer types expressing the most common MR1∗01 and/or MR1∗02 allomorphs (over 95% of the population), while remaining inert to healthy cells including healthy B cells and monocytes. Curiously, in all but one donor these T cells were found to incorporate a conserved TCR-α chain motif, CAXYGGSQGNLIF (where X represents 3-5 amino acids), because of pairing between 10 different TRAV genes and the TRAJ42 gene segment. This semi-invariance in the TCR-α chain is reminiscent of MAIT cells and suggests recognition of a conserved antigen bound to K43.

Original language	English
Article number	e181895
Journal	Journal of Clinical Investigation
Volume	135
Issue number	1
DOIs	https://doi.org/10.1172/JCI181895
Publication status	Published - 2 Jan 2025
Externally published	Yes

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Cite this

Dolton, G., Thomas, H., Tan, L. R., Rafael, C. R., Doetsch, S., Ionescu, G. A., Cardo, L. F., Crowther, M. D., Behiry, E., Morin, T., Caillaud, M. E., Srai, D., Parolini, L., Hasan, M. S., Fuller, A., Topley, K., Wall, A., Hopkins, J. R., Omidvar, N., ... Sewell, A. K. (2025). MHC-related protein 1-restricted recognition of cancer via a semi-invariant TCR-α chain. Journal of Clinical Investigation, 135(1), Article e181895. https://doi.org/10.1172/JCI181895

@article{d021b88a822d4ef2a41f83980712dbed,

title = "MHC-related protein 1-restricted recognition of cancer via a semi-invariant TCR-α chain",

abstract = "The T cell antigen presentation platform MR1 consists of 6 allomorphs in humans that differ by no more than 5 amino acids. The principal function of this highly conserved molecule involves presenting microbial metabolites to the abundant mucosalassociated invariant T (MAIT) cell subset. Recent developments suggest that the role of MR1 extends to presenting antigens from cancer cells, a function dependent on the K43 residue in the MR1 antigen binding cleft. Here, we successfully cultured cancer-activated, MR1-restricted T cells from multiple donors and confirmed that they recognized a wide range of cancer types expressing the most common MR1∗01 and/or MR1∗02 allomorphs (over 95% of the population), while remaining inert to healthy cells including healthy B cells and monocytes. Curiously, in all but one donor these T cells were found to incorporate a conserved TCR-α chain motif, CAXYGGSQGNLIF (where X represents 3-5 amino acids), because of pairing between 10 different TRAV genes and the TRAJ42 gene segment. This semi-invariance in the TCR-α chain is reminiscent of MAIT cells and suggests recognition of a conserved antigen bound to K43.",

author = "Garry Dolton and Hannah Thomas and Tan, {Li Rong} and Rafael, {Cristina Rius} and Stephanie Doetsch and Ionescu, {Giulia Andreea} and Cardo, {Lucia F.} and Crowther, {Michael D.} and Enas Behiry and Th{\'e}o Morin and Caillaud, {Marine E.} and Devinder Srai and Lucia Parolini and Hasan, {Md Samiul} and Anna Fuller and Katie Topley and Aaron Wall and Hopkins, {Jade R.} and Nader Omidvar and Caroline Alvares and Joanna Zabkiewicz and John Frater and Barbara Szomolay and Sewell, {Andrew K.}",

note = "Publisher Copyright: {\textcopyright} 2025, Dolton et al.",

year = "2025",

month = jan,

day = "2",

doi = "10.1172/JCI181895",

language = "English",

volume = "135",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

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Dolton, G, Thomas, H, Tan, LR, Rafael, CR, Doetsch, S, Ionescu, GA, Cardo, LF, Crowther, MD, Behiry, E, Morin, T, Caillaud, ME, Srai, D, Parolini, L, Hasan, MS, Fuller, A, Topley, K, Wall, A, Hopkins, JR, Omidvar, N, Alvares, C, Zabkiewicz, J, Frater, J, Szomolay, B & Sewell, AK 2025, 'MHC-related protein 1-restricted recognition of cancer via a semi-invariant TCR-α chain', Journal of Clinical Investigation, vol. 135, no. 1, e181895. https://doi.org/10.1172/JCI181895

TY - JOUR

T1 - MHC-related protein 1-restricted recognition of cancer via a semi-invariant TCR-α chain

AU - Dolton, Garry

AU - Thomas, Hannah

AU - Tan, Li Rong

AU - Rafael, Cristina Rius

AU - Doetsch, Stephanie

AU - Ionescu, Giulia Andreea

AU - Cardo, Lucia F.

AU - Crowther, Michael D.

AU - Behiry, Enas

AU - Morin, Théo

AU - Caillaud, Marine E.

AU - Srai, Devinder

AU - Parolini, Lucia

AU - Hasan, Md Samiul

AU - Fuller, Anna

AU - Topley, Katie

AU - Wall, Aaron

AU - Hopkins, Jade R.

AU - Omidvar, Nader

AU - Alvares, Caroline

AU - Zabkiewicz, Joanna

AU - Frater, John

AU - Szomolay, Barbara

AU - Sewell, Andrew K.

PY - 2025/1/2

Y1 - 2025/1/2

N2 - The T cell antigen presentation platform MR1 consists of 6 allomorphs in humans that differ by no more than 5 amino acids. The principal function of this highly conserved molecule involves presenting microbial metabolites to the abundant mucosalassociated invariant T (MAIT) cell subset. Recent developments suggest that the role of MR1 extends to presenting antigens from cancer cells, a function dependent on the K43 residue in the MR1 antigen binding cleft. Here, we successfully cultured cancer-activated, MR1-restricted T cells from multiple donors and confirmed that they recognized a wide range of cancer types expressing the most common MR1∗01 and/or MR1∗02 allomorphs (over 95% of the population), while remaining inert to healthy cells including healthy B cells and monocytes. Curiously, in all but one donor these T cells were found to incorporate a conserved TCR-α chain motif, CAXYGGSQGNLIF (where X represents 3-5 amino acids), because of pairing between 10 different TRAV genes and the TRAJ42 gene segment. This semi-invariance in the TCR-α chain is reminiscent of MAIT cells and suggests recognition of a conserved antigen bound to K43.

AB - The T cell antigen presentation platform MR1 consists of 6 allomorphs in humans that differ by no more than 5 amino acids. The principal function of this highly conserved molecule involves presenting microbial metabolites to the abundant mucosalassociated invariant T (MAIT) cell subset. Recent developments suggest that the role of MR1 extends to presenting antigens from cancer cells, a function dependent on the K43 residue in the MR1 antigen binding cleft. Here, we successfully cultured cancer-activated, MR1-restricted T cells from multiple donors and confirmed that they recognized a wide range of cancer types expressing the most common MR1∗01 and/or MR1∗02 allomorphs (over 95% of the population), while remaining inert to healthy cells including healthy B cells and monocytes. Curiously, in all but one donor these T cells were found to incorporate a conserved TCR-α chain motif, CAXYGGSQGNLIF (where X represents 3-5 amino acids), because of pairing between 10 different TRAV genes and the TRAJ42 gene segment. This semi-invariance in the TCR-α chain is reminiscent of MAIT cells and suggests recognition of a conserved antigen bound to K43.

U2 - 10.1172/JCI181895

DO - 10.1172/JCI181895

M3 - Article

C2 - 39744940

AN - SCOPUS:85214334288

SN - 0021-9738

VL - 135

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 1

M1 - e181895

ER -