Biologically relevant orthogonal cytokine/receptor pairs

1. An engineered human IL-2 polypeptide, which comprises amino acid substitutions, numbered relative to reference SEQ ID NO:4:

E15S, E15T, E15Q, or E15H;

H16Q;

L19V or L19I;

D20T, D20S, D20L or D20M; and

M23L, M23S, M23V, M23A, or M23T;

and optionally comprises Q22K, Q22N, R81D, R81Y, T51I or a combination thereof.

2. The engineered human IL-2 polypeptide of claim 1 , comprising amino acid substitution Q22K.

3. The engineered human IL-2 polypeptide of claim 1 , comprising amino acid substitution T51I.

4. The engineered human IL-2 polypeptide of claim 1 , comprising amino acid substitution R81D or R81Y.

5. The engineered human IL-2 polypeptide of claim 1 , wherein the polypeptide binds to and activates an orthogonal human CD122 protein.

6. The engineered human IL-2 polypeptide of claim 5 , wherein the orthogonal human CD122 protein is modified at one or more residues selected from R41, R42, Q70, K71, T73, T74, V75, S132, H133, Y134, F135, E136, Q214.

7. The engineered human IL-2 polypeptide of claim 5 , wherein the orthogonal human CD122 protein is modified at H133 and Y134.

8. The engineered human IL-2 polypeptide of claim 7 , wherein the orthogonal human CD122 protein comprises amino acid substitutions H133D and Y134F.

9. A system for selective activation of a receptor in a cell, the system comprising:

(a) an orthogonal human CD122 receptor comprising amino acid substitutions at H133 and Y134; and

(b) the engineered human IL-2 polypeptide of claim 1 .

10. The system of claim 9 , wherein the orthogonal receptor is expressed by a mammalian cell.

11. The system of claim 10 , wherein the cell is an immune cell or a stem cell.

12. The system of claim 11 , wherein the immune cell is a T cell.

13. A pharmaceutical composition comprising the engineered human IL-2 polypeptide of claim 1 ; and a pharmaceutically acceptable excipient.

14. A kit comprising the system of claim 9 .

15. The engineered human IL-2 polypeptide of claim 1 comprising substitutions Q22K and M23A.

16. The engineered human IL-2 polypeptide of claim 1 comprising substitutions M23Q, R81 D and T51I.

17. The engineered human IL-2 polypeptide of claim 1 comprising substitutions M23Q and R81Y.

18. The engineered human IL-2 polypeptide of claim 1 comprising substitution M23A.

19. An engineered human IL-2 polypeptide that comprises a set of amino acid substitutions, numbered relative to reference SEQ ID NO:4:

E15S;

H16Q;

L19V;

D20L;

M23A; and

Q22K.

20. The engineered human IL-2 polypeptide of claim 1 that comprises a set of amino acid substitutions, numbered relative to reference SEQ ID NO:4:

E15S;

H16Q;

L19V;

D20L;

M23Q;

R81D; and

T51I.

21. The engineered human IL-2 polypeptide of claim 1 that comprises a set of amino acid substitutions, numbered relative to reference SEQ ID NO:4:

E15S;

H16Q;

L19V;

D20L;

M230;

and R81Y.

22. An engineered human IL-2 polypeptide that comprises a set of amino acid substitutions, numbered relative to reference SEQ ID NO:4:

E1 5S;

H16Q;

L19V;

D20L; and

M23A.

23. The engineered human IL-2 polypeptide of claim 1 , wherein the engineered human IL-2 polypeptide is pegylated.

24. The engineered human IL-2 polypeptide of claim 1 , wherein the engineered human IL-2 polypeptide is fused to an Fc domain of IgG or albumin.

25. The engineered human IL-2 protein of claim 19 , wherein the engineered human IL-2 polypeptide is pegylated.

26. The engineered human IL-2 protein of claim 22 , wherein the engineered human IL-2 polypeptide is pegylated.