Methods and Compositions for the Generation and Maintenance of Regulatory T Cells

Abstract

Methods and compositions for generating and maintaining induced regulatory T cells (iTregs) are provided. Methods and compositions for treating an autoimmune disorder, organ transplant rejection, graft versus host disease or allergic or hypersensitivity and inflammation are also provided.

1 .- 11 . (canceled) 
     
     
         12 . A method of culturing a regulatory T cell (Treg) comprising the steps of:
 a) providing a Treg; and   b) incubating the Treg in the presence of PD-L, such that activities of the Treg are retained or enhanced.   
     
     
         13 . The method of  claim 12 , wherein the activities of the Treg is expressing Foxp3 or suppressing Teff activation. 
     
     
         14 . The method of  claim 12 , wherein the Treg is obtained by contacting a naïve T cell with PD-L to induce the naïve T cell to differentiate into a Treg. 
     
     
         15 . The method of  claim 12 , wherein the PD-L is one or both of PD-L1 and PD-L2. 
     
     
         16 . A method of treating an autoimmune disorder in an individual in need thereof comprising contacting naïve T cells within the individual with exogenous PD-L to differentiate the naïve T cells into iTreg, such that one or more symptoms of said autoimmune disorder are reduced in said individual. 
     
     
         17 . The method of  claim 16 , wherein Foxp3 expression is increased in said individual. 
     
     
         18 . The method of  claim 16 , wherein Teff activation is suppressed in said individual. 
     
     
         19 . The method of  claim 16 , wherein the Akt signaling pathway is suppressed in said individual. 
     
     
         20 . The method of  claim 16 , wherein the PD-L is one or both of PD-L1 and PD-L2. 
     
     
         21 . A method of treating an autoimmune disorder in an individual in need thereof comprising administering exogenous iTreg to the individual, such that one or more symptoms of said autoimmune disorder are reduced in said individual. 
     
     
         22 . The method of  claim 21 , wherein Foxp3 expression is increased in said individual. 
     
     
         23 . The method of  claim 21 , wherein Teff activation is suppressed in said individual. 
     
     
         24 . A method of treating an autoimmune disorder in an individual in need thereof comprising contacting the individual with a compound that stimulates one or more PD-L-mediated activities in said individual. 
     
     
         25 . The method of  claim 24 , wherein the compound is a PD-L agonist. 
     
     
         26 . The method of  claim 24 , wherein the PD-L is one or both of PD-L1 and PD-L2. 
     
     
         27 . A method of ameliorating, preventing and/or treating diseases, symptoms and/or disorders associated with an autoimmune disorder, organ transplant rejection, graft versus host disease or allergic or hypersensitivity response in an individual in need thereof comprising administering exogenous PD-L to the individual to differentiate naïve T cells into iTreg, such that one or more diseases, symptoms and/or disorders associated with the autoimmune disorder, organ transplant rejection, graft versus host disease or allergic or hypersensitivity response is reduced or prevented in the individual. 
     
     
         28 . The method of  claim 27 , wherein Foxp3 expression is increased in said individual. 
     
     
         29 . The method of  claim 27 , wherein Teff activation is suppressed in said individual. 
     
     
         30 . The method of  claim 27 , wherein the Akt signaling pathway is suppressed in said individual. 
     
     
         31 . The method of  claim 27 , wherein the PD-L is one or both of PD-L1 and PD-L2. 
     
     
         32 . A method of ameliorating, preventing and/or treating diseases, symptoms and/or disorders associated with an autoimmune disorder, organ transplant rejection, graft versus host disease or allergic or hypersensitivity response in an individual in need thereof comprising administering exogenous iTreg to the individual such that one or more diseases, symptoms and/or disorders associated with the autoimmune disorder, organ transplant rejection, graft versus host disease or allergic or hypersensitivity response is reduced or prevented in the individual. 
     
     
         33 . The method of  claim 32 , wherein Foxp3 expression is increased in said individual. 
     
     
         34 . The method of  claim 32 , wherein Teff activation is suppressed in said individual. 
     
     
         35 . The method of  claim 32 , wherein the Akt signaling pathway is suppressed in said individual. 
     
     
         36 . A method of ameliorating, preventing and/or treating immune responses in tissue, comprising contacting the tissue with exogenous PD-L or exogenous iTreg at the site of tissue inflammation such that the inflammation is reduced. 
     
     
         37 . The method of  claim 36 , wherein the tissue is eye tissue. 
     
     
         38 . The method of  claim 36 , wherein the PD-L is one or both of PD-L1 and PD-L2. 
     
     
         39 . A method of generating an iTreg comprising the steps of:
 a) providing an naïve T cell; and   b) differentiating the naïve T cell into an iTreg by contacting the naïve T cell with an agonistic anti-PD-L monoclonal antibody (mAb).   
     
     
         40 . The method of  claim 39 , wherein the iTreg expresses Foxp3. 
     
     
         41 . The method of  claim 39 , wherein the mAb is an anti-PD-L1 antibody or an anti-PD-L2 antibody. 
     
     
         42 . The method of  claim 25 , wherein the PD-L agonist is a mAb against PD-1. 
     
     
         43 . The method of  claim 42 , wherein the mAb against PD-1 delivers a signal into naïve T cells after activation or into regulatory T cells that express PD-1.