Modulation of T cell signaling via slat association with IP3R1
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Publication Number
US-10774143-B1
Publication Date
2020-09-15
Expiration Date
Abstract
Methods of modulating immune responses are provided, including contacting SLAT or IP3R1 with an agent that modulates binding of SLAT to IP3R1. Methods of modulating activation or differentiation of CD4+ T cells are also provided, including contacting SLAT or IP3R1 with an agent that modulates binding of SLAT to IP3R1. Peptides and fragments of an IP3R1 amino acid sequence that binds to a SLAT amino acid sequence, and peptides and fragments of a SLAT amino acid sequence that binds to am IP3R1 amino acid sequence, are further provided.
Core Innovation
TCR stimulation in CD4+ T cells is disclosed to drive a direct, Ca2+-sensitive association between SLAT (Def6/IBP) and IP3R1 (IP3 receptor type I). The association is mediated by SLAT EF-hand and PH domains and by a conserved short motif within the IP3R1 ligand-binding domain, described as IP3R1 residues 400–417. This linkage defines a specific SLAT–IP3R1 interaction that is sensitive to Ca2+.
The disclosed functional inhibition uses a cell-permeable TAT-fused peptide (TAT-HA-2.1 containing IP3R1 f2.1) that reduces the SLAT–IP3R1 interaction. The reduction of the interaction is disclosed to inhibit TCR-induced Ca2+/NFAT signaling. The same disruption is further disclosed to lower cytokine production, including IFNγ.
The disclosed results are stated to lower cytokine production without altering proximal TCR phosphorylation. The patent text further discloses that agents modulating SLAT–IP3R1 binding can be used to modulate immune responses and CD4+ T cell activation and differentiation by contacting SLAT or IP3R1 with such agents, including peptides/fragments and other binding-modulatory modalities. Methods for screening and identifying agents that modulate SLAT–IP3R1 binding are also described.
Claims Coverage
The provided independent claims cover a method of decreasing or inhibiting immune responses by contacting SLAT with a defined, fused peptide, with four main inventive constraints: (i) SLAT-contacting, (ii) peptide definition by SEQ ID NO:4 with a length constraint relative to SEQ ID NO:3, (iii) fusion to a cell-penetrating or cell-targeting moiety, and (iv) functional outcome of decreasing/inhibiting immune response or decreasing/inhibiting CD4+ T cell activation or differentiation.
SLAT-contacting with a defined SEQ ID peptide
A method of decreasing, reducing, or inhibiting an immune response comprising contacting SLAT (SWAP-70-like adaptor of T cells) with a sufficient amount of a peptide.
Peptide length and sequence defined by SEQ ID NO:4 and SEQ ID NO:3
The peptide has a length less than or equal to the sequence of SEQ ID NO:3, wherein the peptide comprises SEQ ID NO:4.
Peptide fused to a cell-penetrating or cell-targeting moiety
The peptide is fused to a cell-penetrating or cell targeting moiety.
Decreasing, reducing, or inhibiting an immune response
The contacting decreases, reduces, or inhibits an immune response.
Inhibiting activation or differentiation of CD4+ T cells
A method of decreasing or inhibiting activation or differentiation of CD4+ T cells comprising contacting SLAT (SWAP-70-like adaptor of T cells) with a sufficient amount of a peptide, wherein the contacting thereby decreases or inhibits activation or differentiation of CD4+ T cells.
Across the independent claims, the coverage centers on contacting SLAT with a peptide comprising SEQ ID NO:4 and constrained by the peptide length relative to SEQ ID NO:3, where the peptide is fused to a cell-penetrating or cell-targeting moiety, resulting in decreased/inhibited immune response or decreased/inhibited CD4+ T cell activation or differentiation.
Stated Advantages
Decreases, reduces, or inhibits an immune response.
Decreases or inhibits activation or differentiation of CD4+ T cells.
Inhibits TCR-induced Ca2+/NFAT signaling.
Lowers cytokine production, including IFNγ.
Reduces SLAT–IP3R1 interaction without altering proximal TCR phosphorylation.
Documented Applications
Modulating immune responses by contacting SLAT or IP3R1 with agents that modulate SLAT–IP3R1 binding.
Modulating CD4+ T cell activation/differentiation by contacting SLAT or IP3R1 with binding-modulatory agents.
Screening/identification of agents that modulate SLAT–IP3R1 binding.
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