Methods and compositions for increasing the suppressive function of regulatory T-cells (Tregs)
Methods and compositions for increasing the suppressive function of regulatory T-cells (Tregs) are provided.
1. A method of reducing or eliminating a cytoskeleton protein in Treg cells, comprising: contacting the Treg cells with a cytoskeleton protein-specific inhibitory nucleic acid molecule, wherein the cytoskeleton protein is a type III intermediate filament protein, and wherein the type III intermediate filament protein is vimentin.
2. The method of claim 1 , wherein the cytoskeleton protein-specific inhibitory nucleic acid molecule is a RNAi nucleic acid molecule.
3. The method of claim 1 , wherein the cytoskeleton protein-specific inhibitory nucleic acid molecule is an antisense nucleic acid molecule.
4. The method of claim 1 , wherein the cytoskeleton protein-specific inhibitor nucleic acid molecule is a siRNA nucleic acid molecule.
5. The method of claim 1 , wherein the vimentin-specific inhibitory nucleic acid molecule has the sequence shown in SEQ ID NO: 13, 14, 15 or 16.
6. The method of claim 1 , wherein the Treg cells are contacted in vitro.
7. The method of claim 1 , wherein the Treg cells are contacted in situ.
8. The method of claim 1 , wherein the Treg cells are contacted in vivo in an individual who has received or is receiving a bone marrow transplant.
9. The method of claim 1 , wherein the Treg cells exhibit a phenotype of at least one of the following:
reduced PKC-θ auto-phosphorylation at Ser676;
improved ability to suppress CD4+ and CD8+ Tcon proliferation;
increased surface expression of Nrp1;
increased surface expression of Lag3;
increased basal and maximal oxygen consumption rate (OCR);
increased BoDipy C1-C12 uptake;
increased expression of CD71;
increased expression of CD98;
increased expression of CPT1a; or
reduced activity of mTORC2, relative to Tregs that lack the cytoskeleton protein-specific inhibitory nucleic acid molecule.
10. A method of increasing or augmenting the suppressor cell potency of Treg cells, comprising: reducing or eliminating vimentin in the Treg cells, wherein reducing or eliminating the vimentin in the Treg cells comprises contacting the Treg cells with a nucleic acid.
11. The method of claim 10 , wherein the nucleic acid is a vimentin-specific inhibitory nucleic acid molecule.
12. The method of claim 11 , wherein the vimentin-specific inhibitory nucleic acid molecule is a siRNA nucleic acid molecule.
13. The method of claim 10 , wherein the method is performed in vitro.
14. The method of claim 10 , wherein the method is performed in situ.
15. The method of claim 14 , wherein the method is performed on an individual who has received or is receiving a bone marrow transplant.
16. The method of claim 10 , wherein the Treg cells in which the vimentin has been reduced or eliminated exhibit a phenotype of at least one of the following:
reduced PKC-θ auto-phosphorylation at Ser676;
improved ability to suppress CD4+ and CD8+ Tcon proliferation;
increased surface expression of Nrp1;
increased surface expression of Lag3;
increased basal and maximal oxygen consumption rate (OCR);
increased BoDipy C1-C12 uptake;
increased expression of CD71;
increased expression of CD98;
increased expression of CPT1a; or
reduced activity of mTORC2, relative to Tregs in which vimentin is not reduced or eliminated.