METHODS FOR CONTROLLING T CELL PROLIFERATION

1 - 23 . (canceled)

24 . A nucleic acid comprising a polynucleotide encoding a chimeric signaling molecule, wherein the chimeric signaling molecule comprises

a) an intracellular FKBP12 polypeptide or FKBP12 variant polypeptide multimerizing region that binds to a multimeric ligand;

b) a first co-stimulatory polypeptide cytoplasmic signaling region selected from the group consisting of CD27, CD28, CD40, ICOS, 4-1BB, CD40, RANK/TRANCE-R, and OX40; and

c) a second co-stimulatory polypeptide cytoplasmic signaling region selected from the group consisting of CD27, CD28, CD40, ICOS, 4-1BB, CD40, RANK/TRANCE-R, and OX40;

wherein

the chimeric signaling molecule lacks an extracellular domain or does not have a functional extracellular domain, and

the chimeric signaling molecule oligomerizes upon binding of the multimerizing region to the multimeric ligand.

25 . The nucleic acid of claim 24 , wherein the multimeric ligand is AP1903.

26 . The nucleic acid of claim 24 , wherein the FKBP12 variant polypeptide comprises a modified FKBP12 polypeptide comprising an amino acid substitution at position 36 that binds with higher affinity to AP1903 than the wild type FKBP12 polypeptide.

27 . The nucleic acid of claim 26 , wherein the FKBP12 variant polypeptide comprises FKBP12v36.

28 . The nucleic acid of claim 24 , wherein the multimerizing region comprises two FKBP12v36 polypeptides.

29 . The nucleic acid of claim 24 , comprising a promoter sequence operably linked to the polynucleotide.

30 . The nucleic acid of claim 24 , wherein the chimeric signaling molecule comprises a membrane-targeting region selected from the group consisting of myristoylation-targeting sequence, palmitoylation-targeting sequence, and prenylation sequence.

31 . The nucleic acid of claim 30 , wherein the membrane-targeting region comprises a myristoylation-targeting sequence.

32 . The nucleic acid of claim 24 , wherein the co-stimulatory polypeptide cytoplasmic signaling regions comprise a CD28 cytoplasmic signaling region and a 4-1BB cytoplasmic signaling region.

33 . A modified cell comprising a nucleic acid of claim 24 , wherein the cell is selected from the group consisting of T cells, NK T cells, and NK cells.

34 . A method for making modified cell of claim 33 , comprising transfecting or transducing a T cell, an NK T cell, or an NK cell in vitro or ex vivo with a nucleic acid comprising a polynucleotide encoding a chimeric signaling molecule, wherein the chimeric signaling molecule comprises

a) an intracellular FKBP12 polypeptide or FKBP12 variant polypeptide multimerizing region that binds to a multimeric ligand;

b) a first co-stimulatory polypeptide cytoplasmic signaling region selected from the group consisting of CD27, CD28, CD40, ICOS, 4-1BB, CD40, RANK/TRANCE-R, and OX40; and

c) a second co-stimulatory polypeptide cytoplasmic signaling region selected from the group consisting of CD27, CD28, CD40, ICOS, 4-1BB, CD40, RANK/TRANCE-R, and OX40;

wherein

the chimeric signaling molecule lacks an extracellular domain or does not have a functional extracellular domain, and

the chimeric signaling molecule oligomerizes upon binding of the multimerizing region to a multimeric ligand.

35 . A modified cell comprising a nucleic acid that comprises a polynucleotide encoding a chimeric signaling molecule, wherein:

a) the cell is selected from the group consisting of T cells, NK T cells, and NK cells; and

b) the chimeric signaling molecule comprises

ii) an intracellular FKBP12 polypeptide or FKBP12 variant polypeptide multimerizing region that binds to a multimeric ligand; and

iii) co-stimulatory polypeptide cytoplasmic signaling region selected from the group consisting of CD27, CD28, ICOS, 4-1BB, CD40, RANK/TRANCE-R, and OX40

wherein

the chimeric signaling molecule lacks an extracellular domain or does not have a functional extracellular domain, and

the chimeric signaling molecule oligomerizes upon binding of the multimerizing region to the multimeric ligand.