Discovery of regulatory t cells programmed to suppress an immune response

Abstract

A method to treat an autoimmune disease is provided. The method involves administration of interleukin-15 receptor (IL-15R) agonists in an amount effective to ameliorate a symptom of the autoimmune disease. The invention also involves a method to treat an autoimmune disease by ex-vivo expansion of CD44+CD122+Kir+ CD8+ Treg cells and administration of the CD44+CD122+Kir+ CD8+ Treg cells. Compositions comprising CD44+CD122+Kir+ CD8+ Treg cells are also provided. Methods for stimulating an immune response to an antigen are also provided.

We claim: 
     
         1 . A method for treating an autoimmune disease comprising:
 administering to a subject in need of such treatment an interleukin-15 receptor (IL-15R) agonist in an amount effective to ameliorate a symptom of the autoimmune disease.   
     
     
         2 . The method of  claim 1 , wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, chronic graft versus host disease, rheumatoid arthritis, insulin-dependent diabetes mellitus, multiple sclerosis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Graves disease, Crohn's disease, Waldenstrom's macroglobulinemia, hyperviscosity syndrome, monoclonal gammopathy of undetermined origin, POEMS syndrome, myeloma, macroglobulinemia, and cold agglutinin disease. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the agonist is a IL-15 polypeptide that comprises a sequence at least 90% identical to the amino acid sequence of SEQ ID NO:1 (IL-15) and binds an IL-15R. 
     
     
         5 . The method of  claim 1 , wherein the agonist is an anti-IL15R antibody or an antigen-binding fragment thereof. 
     
     
         6 . The method of  claim 1 , wherein the agonist is a heterocomplex of IL-15 linked to soluble IL-15 receptor alpha chain via a GS linker. 
     
     
         7 . A method for treating an autoimmune disease in a subject comprising:
 a. isolating T cells from the subject in need of such treatment, wherein the isolated T cells comprise a number of CD44+CD122+Helios+CD8+ Treg cells;   b. growing the isolated cells in a culture medium containing IL-15 and IL-21 in the presence of Concavalin A activated and irradiated syngenic CD4 T cells until the number of CD44+CD122+Helios+CD8+ Treg cells increases by at least 5%, thereby producing a population of cells enriched with CD44+CD122+Helios+ CD8+ Treg cells;   c. administering CD44+CD122+Helios+ CD8+ Treg cells from the population of cells to the subject in an amount effective to ameliorate a symptom of the autoimmune disease.   
     
     
         8 . The method of  claim 7 , wherein the CD44+CD122+Helios+ CD8+ Treg cells are Kir+. 
     
     
         9 - 12 . (canceled) 
     
     
         13 . A method for treating an autoimmune disease in a subject comprising:
 a. isolating T cells from the subject in need of such treatment, wherein the isolated T cells comprise a number of CD44+CD122+Kir+CD8+ Treg cells;   b. growing the isolated cells in a culture medium containing IL-15 and IL-21 in the presence of Concavalin A activated and irradiated syngenic CD4 T cells until the number of CD44+CD122+Kir+CD8+ Treg cells increases by at least 5%, thereby producing a population of cells enriched with CD44+CD122+Kir+ CD8+ Treg cells;   c. administering CD44+CD122+Kir+ CD8+ Treg cells from the population of cells to the subject in an amount effective to ameliorate a symptom of the autoimmune disease.   
     
     
         14 - 17 . (canceled) 
     
     
         18 . A composition comprising CD8+ cells, wherein at least 5% of the CD8+ cells in the composition are CD44+CD122+Helios+ CD8+ Treg cells. 
     
     
         19 . The composition of  claim 18 , wherein the CD44+CD122+Helios+ CD8+ Treg cells are Kir+. 
     
     
         20 . A composition comprising CD8+ cells, wherein at least 5% of the CD8+ cells in the composition are CD44+CD122+Kir+ CD8+ Treg cells. 
     
     
         21 - 24 . (canceled) 
     
     
         25 . A method for stimulating an immune response to an antigen comprising:
 administering to a subject having the antigen and in need of immune stimulation to the antigen an agent that inhibits the proliferation and/or activity of CD44+CD122+CD8+ Treg cells in an amount effective to stimulate an immune response in the subject to the antigen, wherein the CD44+CD122+CD8+ Treg cells are Helios+ and/or Kir+.   
     
     
         26 - 27 . (canceled) 
     
     
         28 . The method of  claim 25 , wherein the antigen is administered to the subject in a vaccine. 
     
     
         29 . The method of  claim 25 , wherein the agent is an anti IL-15 antibody. 
     
     
         30 . The method of  claim 25 , wherein the CD44+CD122+CD8+ Treg cells are Kir+ and the agent is an antibody that binds CD44+CD122+Kir+CD8+ Treg cells. 
     
     
         31 . The method of  claim 25 , wherein the CD44+CD122+CD8+ Treg cells are Helios+ and the agent inhibits the expression and/or activity of Helios. 
     
     
         32 . The method of  claim 30 , wherein and the antibody is a bispecific antibody comprising:
 a first antigen-binding domain that binds to a first surface marker present on the CD44+CD122+ Kir+CD8+ Treg cells; and   a second antigen-binding domain that binds to a second surface marker present on the CD44+CD122+Kir+CD8+ Treg cells.   
     
     
         33 . The method of  claim 32 , wherein the first and second surface markers on the CD44+CD122+Kir+ CD8+ Treg cells are selected from the group consisting of CD44, CD122, Kir and CD8. 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 25 , wherein the agent is a composition comprising
 a sub-optimal dose of a first antibody that binds a first surface antigen present on CD44+CD122+CD8+ Treg cells, and   a sub-optimal dose of a second antibody that binds a second surface antigen present on the CD44+CD122+CD8+ Treg cells, wherein the first surface antigen is different from the second surface antigen.   
     
     
         36 . The method of  claim 35 , wherein the first antibody binds an antigen selected from the group consisting of CD44, CD122, Kir and CD8 and the second antibody binds an antigen selected from the group consisting of CD44, CD122, Kir and CD8. 
     
     
         37 . (canceled)