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Generation of higher affinity T cell receptors by antigen-driven differentiation of progenitor T cells in vitro.

Abstract：

:Many promising targets for T-cell-based cancer immunotherapies are self-antigens. During thymic selection, T cells bearing T cell receptors (TCRs) with high affinity for self-antigen are eliminated. The affinity of the remaining low-avidity TCRs can be improved to increase their antitumor efficacy, but conventional saturation mutagenesis approaches are labor intensive, and the resulting TCRs may be cross-reactive. Here we describe the in vitro maturation and selection of mouse and human T cells on antigen-expressing feeder cells to develop higher-affinity TCRs. The approach takes advantage of natural Tcrb gene rearrangement to generate diversity in the length and composition of CDR3β. In vitro differentiation of progenitors transduced with a known Tcra gene in the presence of antigen drives differentiation of cells with a distinct agonist-selected phenotype. We purified these cells to generate TCRβ chain libraries pre-enriched for target antigen specificity. Several TCRβ chains paired with a transgenic TCRα chain to produce a TCR with higher affinity than the parental TCR for target antigen, without evidence of cross-reactivity.

journal_name

Nat Biotechnol

journal_title

Nature biotechnology

authors

Schmitt TM,Aggen DH,Ishida-Tsubota K,Ochsenreither S,Kranz DM,Greenberg PD

doi

10.1038/nbt.4004

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

1188-1195

issue

12

eissn

1087-0156

issn

1546-1696

pii

nbt.4004

journal_volume

35

pub_type

杂志文章

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