The T cell receptor sequence influences the likelihood of T cell memory formation

Kaitlyn A Lagattuta; Ayano C Kohlgruber; Nouran S Abdelfattah; Aparna Nathan; Laurie Rumker; Michael E Birnbaum; Stephen J Elledge; Soumya Raychaudhuri

doi:10.1016/j.celrep.2024.115098

The T cell receptor sequence influences the likelihood of T cell memory formation

Cell Rep. 2025 Jan 28;44(1):115098. doi: 10.1016/j.celrep.2024.115098. Epub 2024 Dec 27.

Authors

Kaitlyn A Lagattuta¹, Ayano C Kohlgruber², Nouran S Abdelfattah³, Aparna Nathan¹, Laurie Rumker¹, Michael E Birnbaum⁴, Stephen J Elledge⁵, Soumya Raychaudhuri⁶

Affiliations

¹ Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
² Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA; Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
³ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁴ Koch Institute for Integrative Cancer Research, Cambridge, MA, USA; Department of Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
⁵ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
⁶ Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: soumya@broadinstitute.org.

Abstract

The amino acid sequence of the T cell receptor (TCR) varies between T cells of an individual's immune system. Particular TCR residues nearly guarantee mucosal-associated invariant T (MAIT) and natural killer T (NKT) cell transcriptional fates. To define how the TCR sequence affects T cell fates, we analyze the paired αβTCR sequence and transcriptome of 961,531 single cells. We find that hydrophobic complementarity-determining region (CDR)3 residues promote regulatory T cell fates in both the CD8 and CD4 lineages. Most strikingly, we find a set of TCR sequence features that promote the T cell transition from naive to memory. We quantify the extent of these features through our TCR scoring function "TCR-mem." Using TCR transduction experiments, we demonstrate that increased TCR-mem promotes T cell activation, even among T cells that recognize the same antigen. Our results reveal a common set of TCR sequence features that enable T cell activation and immunological memory.

Keywords: CP: Immunology; T-cells; TCR; activation; immunology; memory; transcriptomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
CD8-Positive T-Lymphocytes / immunology
Complementarity Determining Regions / immunology
Immunologic Memory* / immunology
Lymphocyte Activation / immunology
Memory T Cells* / immunology
Mice
Mice, Inbred C57BL
Receptors, Antigen, T-Cell* / chemistry
Receptors, Antigen, T-Cell* / genetics
Receptors, Antigen, T-Cell* / immunology
Receptors, Antigen, T-Cell* / metabolism
Receptors, Antigen, T-Cell, alpha-beta

Substances

Receptors, Antigen, T-Cell
Complementarity Determining Regions
Receptors, Antigen, T-Cell, alpha-beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding