COMPOSITIONS AND METHODS FOR MODULATING AN IMMUNE RESPONSE
The invention generally features compositions and methods for modulating an immune response. In particular embodiments, such compositions and methods modulate regulatory T cell suppressive activity.
1 . A method for modulating CD4 + CD25 + regulatory T cell (Treg) biological function, the method comprising contacting the cell with an agent that alters Helios expression, thereby modulating CD4 + CD25 + T cell biological function.
2 . The method of claim 1 , wherein the method increases or reduces Treg suppressive activity.
3 . A method for increasing an effector T cell-mediated immune response, the method comprising contacting the cell with an agent that reduces Helios expression or biological activity, thereby increasing the immune response.
4 . The method of claim 3 , wherein the method reduces Treg suppression of an effector T cell mediated immune response.
5 . The method of claim 3 , wherein the method reduces Treg suppressive activity or enhances an effector T cell-mediated immune response.
6 . The method of claim 1 , wherein the agent is a polypeptide, polynucleotide, or small compound.
7 . The method of claim 6 , wherein the agent is a polynucleotide is an inhibitory nucleic acid molecule selected from the group consisting of siRNA, shRNA, or antisense oligonucleotide.
8 . The method of claim 6 , wherein the agent disrupts Helios binding to a FoxP3 promoter.
9 . The method of claim 8 , wherein the agent specifically binds a Helios polypeptide.
10 . The method of claim 8 , wherein the agent binds the FoxP3 promoter at about nucleotides −1184 to −724 and/or −692 to −335 from transcriptional start site.
11 . A method for modulating an effector T cell-mediated immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent that modulates Helios expression or biological activity, thereby modulating the immune response, or
A method for increasing an effector T cell-mediated immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent that reduces Helios expression or biological activity, thereby increasing the immune response, or
A method for treating neoplasia in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent that reduces Helios expression or biological activity, thereby treating the neoplasia, or
A method for increasing the efficacy of an anti-neoplasia vaccine in a subject, the method comprising administering to the subject a vaccine comprising a tumor antigen and an agent that reduces the level or activity of a Helios polypeptide in a cell of the subject.
12 . The method of claim 11 , wherein the method increases or reduces Treg suppressive activity.
13 . The method of claim 11 , wherein the subject is identified as having a neoplasia or pathogen infection.
14 . The method of claim 11 , wherein the subject is identified as having an autoimmune or inflammatory disease.
15 - 23 . (canceled)
24 . The method of claim 11 , wherein the agent binds the FoxP3 promoter at about nucleotides −1184 to −724 and/or −692 to −335 from transcriptional start site and disrupts a Helios/FoxP3 interaction.
25 - 28 . (canceled)
29 . An inhibitory nucleic acid molecule that specifically binds a Helios polynucleotide sequence.
30 . The inhibitory nucleic acid molecule of claim 29 , wherein the inhibitory nucleic acid molecule is an antisense oligonucleotide, siRNA, or shRNA.
31 . The inhibitory nucleic acid molecule of claim 29 , wherein the inhibitory nucleic acid molecule is an siRNA having the following polynucleotide sequence:
Sense: CCUCACAAGUGCAACUACUtt
Antisense: AGUAGUUGCACUUGUGAGGtt
32 . The inhibitory nucleic acid molecule of claim 29 , wherein the inhibitory nucleic acid further comprises an aptamer that specifically binds to an immune cell.
33 - 37 . (canceled)
38 . A vector encoding the inhibitory nucleic acid molecule of claim 29 , or
an expression vector comprising a nucleic acid molecule encoding a Helios polypeptide, or
A pharmaceutical composition for modulating an immune response comprising an effective amount of an agent that reduces the expression or activity of a Helios polypeptide.
39 - 49 . (canceled)
50 . A method for identifying an agent that modulates Treg suppressive activity, the method comprising:
(a) contacting a cell expressing a Helios nucleic acid molecule or polypeptide with a candidate agent; and
(b) detecting an alteration in the level of Helios polynucleotide or polypeptide in the contacted cell relative to the level in an untreated control cell, wherein an alteration in Helios expression identifies the agent as useful for modulating Treg suppressive activity, or
A method for identifying a candidate compound that increases an effector T cell-mediated immune response, the method comprising the steps of:
(a) contacting a cell expressing a Helios polypeptide or polynucleotide with a candidate agent; and
(b) detecting a decrease in the level or biological activity of a Helios polypeptide or polynucleotide in the cell relative to an uncontacted control cell, wherein a decrease in the level or biological activity of the Helios polypeptide identifies the agent as useful for increasing the immune response.
51 - 57 . (canceled)