Modified T cells and methods of their use
The invention provides modified an isolated T lymphocytes having reduced or eliminated expression of the T Cell Receptor, due to reduced or eliminated expression of a CD3ζ, T Cell Receptor Alpha Chain, or T Cell Receptor Beta Chain gene relative to a T lymphocyte without modification, where the isolated T lymphocyte expresses a protein comprising US6, UL40 viral protein and signal peptide, and UL18.
1 . An isolated T lymphocyte modified to have reduced or eliminated expression of the T Cell Receptor (TCR), due to reduced or eliminated expression of a CD3ζ, T Cell Receptor Alpha Chain (TRAC), or T Cell Receptor Beta Chain (TRBC) gene relative to a T lymphocyte without modification, wherein the isolated T lymphocyte expresses a protein comprising US6, UL40 viral protein and signal protein peptide, and UL18.
2 . The isolated T lymphocyte of claim 1 , comprising a genome in which a CD3ζ, TRAC, and/or TRBC gene, regulatory sequence, coding sequence, exon, or a portion thereof, is mutated, resulting in reduced, null, or non-functional CD3ζ, CD3eta, CD3theta, TRAC, or TRBC expression relative to a T lymphocyte without modification.
3 . The isolated T lymphocyte of claim 2 , wherein the mutation is a deletion or a frame shift mutation.
4 . The isolated T lymphocyte of claim 2 , wherein the mutation disrupts assembly of the T cell receptor or CD3ζ signaling.
5 . The isolated T lymphocyte of claim 1 , comprising a genome in which a CD3ζ, TRAC, TRBC gene is deleted.
6 . The isolated T lymphocyte of claim 5 , comprising a genome in which two alleles of a CD3ζ, TRAC, or TRBC gene are deleted.
7 . The isolated T lymphocyte of claim 1 , wherein the reduced expression of the CD3ζ, TRAC, or TRBC gene is null expression.
8 . The isolated T lymphocyte of claim 1 , wherein an HLA locus, or a portion thereof, is deleted.
9 . The isolated T lymphocyte of claim 8 , wherein the HLA locus is on chromosome 6.
10 . The isolated T lymphocyte of claim 1 , further having decreased HLA Class I expression relative to a T lymphocyte without modification.
11 . The isolated T lymphocyte of claim 1 , wherein the isolated T lymphocyte is further modified to express HLA-G.
12 . The isolated T lymphocyte of claim 1 , further comprising a gene encoding a heterologous protein that facilitates the T lymphocyte in evading immune attack from a host to whom the T lymphocyte is administered.
13 . The isolated T lymphocyte of claim 12 , wherein the heterologous protein facilitates evasion of T cell or NK mediated rejection.
14 . The isolated T lymphocyte of claim 1 , further comprising a gene encoding a therapeutic protein.
15 . The isolated T lymphocyte of claim 1 , further comprising a gene that induces cell death.
16 . The isolated T lymphocyte of claim 1 , wherein the T lymphocyte has reduced or eliminated expression of a CD3ζ relative to a T lymphocyte without modification.
17 . The isolated T lymphocyte of claim 1 , wherein the isolated T lymphocyte expresses full length US6, UL40 viral protein and signal peptide, and UL18 having 90% sequence identity respectively to SEQ ID NO: 1, 5, and 6.