Cal-t constructs and uses thereof

Abstract

The technology described herein is directed to compositions comprising components of multi-component CALs or CARs, e.g., a TCR recognition domain; and one or both of: (a) an intracellular signaling domain; and (b) a first-type protein interaction domain. Further provided herein are methods for treating or preventing an autoimmune disease, a transplant rejection, or graft versus host disease.

We claim: 
     
         1 . A method of treating or preventing an autoimmune disease; T cell mediated inflammation or immune response; malignant T cell condition; transplant rejection; or GvHD in a subject in need thereof, the method comprising:
 a) administering to the subject:
 i) a soluble extracellular molecule or a soluble extracellular complex comprising:
 one or more TCR recognition domains that binds specifically to a variable region of a TCR on target cells, and 
 a first biomolecular interaction domain of a binding pair of biomolecular interaction domains; and 
 
 ii) an engineered cell expressing or comprising an engineered signaling polypeptide comprising:
 an extracellular second biomolecular interaction domain of the binding pair of biomolecular interaction domains, and 
 an intracellular signaling domain. 
 
   
     
     
         2 . The method of  claim 1 , wherein the method is characterized in that it exhibits cell killing activity, anergy, or suppression against a population of the target cells expressing the variable region of the TCR. 
     
     
         3 . The method of  claim 1 , wherein the method comprises contacting the target cell with the soluble extracellular molecule or the soluble extracellular complex. 
     
     
         4 . The method of  claim 2 , wherein the method comprises binding of the first biomolecular interaction domain of a binding pair of biomolecular interaction domains of the soluble extracellular molecule or the soluble extracellular complex with the engineered cell expressing or comprising an engineered signaling polypeptide comprising the extracellular second biomolecular interaction domain of the binding pair of biomolecular interaction domains. 
     
     
         5 . The method of  claim 1 , wherein the soluble extracellular molecule or the soluble extracellular complex is selected from one or more donor-derived TCR recognition domains. 
     
     
         6 . The method of  claim 5 , wherein the TCR recognition domain is identified in a donor-derived library. 
     
     
         7 . The method of  claim 1 , wherein the TCR recognition domain is selected from a library of TCR recognition domains associated with the autoimmune disease; T cell mediated inflammation or immune response; malignant T cell condition; transplant rejection; or GvHD. 
     
     
         8 . The method of  claim 1 , wherein the TCR recognition domain comprises a MHC (Major Histocompatibility Complex); a MHC-peptide complex; a featureless peptide MHC; or a MHC-peptide fusion. 
     
     
         9 . The method of  claim 8 , wherein the featureless peptide MHC is a peptide in which anchor residues are preserved, while interfacial residues of the peptide are modified. 
     
     
         10 . The method of  claim 9 , wherein the interfacial residues are modified to alanine or glycine residues. 
     
     
         11 . The method of  claim 9 , wherein the modified interfacial residues prevent TCR binding. 
     
     
         12 . The method of  claim 8 , wherein the featureless peptide MHC is used for transplantation tolerance. 
     
     
         13 . The method of  claim 8 , wherein the featureless peptide MHC comprises a relevant donor-mismatched featureless peptide-MHC soluble extracellular molecule or soluble extracellular complex. 
     
     
         14 . The method of  claim 13 , wherein the method comprises selective depletion of the subject's alloreactive T cells targeted towards a relevant donor-mismatched HLA allele in the subject receiving MHC-mismatched solid organ or hematopoietic stem cell transplants by the relevant donor-mismatched featureless peptide-MHC soluble extracellular molecule or soluble extracellular complex. 
     
     
         15 . The method of  claim 8 , wherein the peptide is a Minor Histocompatibility Antigen (MiHA). 
     
     
         16 . The method of  claim 1 , wherein the TCR recognition domain comprises a donor-derived MHC. 
     
     
         17 . The method of  claim 8 , wherein the MHC and/or the peptide is synthetic. 
     
     
         18 . The method of  claim 1 , wherein the TCR recognition domain comprises a CD1 domain or a CD1 domain-ligand complex or fusion. 
     
     
         19 . The method of  claim 18 , wherein the CD1 is CD1d. 
     
     
         20 . The method of  claim 1 , wherein the TCR recognition domain is a monomer, a dimer, a trimer, a tetramer, a pentamer, a dextramer, or an other oligomer form. 
     
     
         21 . The method of  claim 1 , wherein the intracellular signaling domain is selected from: TCRζ, FcRγ, FcRβ, CD3γ; CD35; CD3ζ; CD3C; CD22; CD79a; CD79b; CD66d; CARD11; CD2; CD7; CD27; CD28; CD30; CD40; CD54 (ICAM); CD83; CD134 (OX40); CD137 (4-1BB); CD150 (SLAMF1); CD152 (CTLA4); CD223 (LAG3); CD270 (HVEM); CD273 (PD-L2); CD274 (PD-L1); CD278 (ICOS); DAP10; LAT; KD2C SLP76; TRIM; and ZAP70. 
     
     
         22 . The method of  claim 1 , wherein the engineered cell is a NK cell, a dendritic cell, or a T cell. 
     
     
         23 . The method of  claim 22 , wherein the T cell is a regulatory T cell or an effector T cell. 
     
     
         24 . The method of  claim 1 , wherein the engineered cell is a chimeric antigen receptor (CAR) T-cell. 
     
     
         25 . The method of  claim 1 , wherein the engineered cell is further engineered to knockdown the native MHCI/II expressed on the cell surface. 
     
     
         26 . The method of  claim 1 , wherein the one or more TCR recognition domains bind specifically to a variable region of a TCR on a population of target cells. 
     
     
         27 . The method of  claim 26 , wherein the population of target cells comprises alloreactive T-cells or autoreactive T-cells. 
     
     
         28 . The method of  claim 26 , wherein the population of target cells comprises one or more of: T-cells, 1E6 T-cells, alloreactive T-cells, autoreactive T-cells, B cell, T cell (CD4 or CD8), regulatory T cell, antigen-presenting cell, dendritic cell, monocyte, macrophage, NKT cell, NK cell, basophil, eosinophil, or neutrophil. 
     
     
         29 . The method of  claim 2 , wherein the cell killing activity, anergy, or suppression against the population of the target cells expressing the variable region of the TCR is modulated by the concentration of the soluble extracellular molecule or the soluble extracellular complex. 
     
     
         30 . The method of  claim 2 , wherein the cell killing activity, anergy, or suppression against the population of the target cells expressing the variable region of the TCR is tunable through modulation of:
 a) the concentration of the one or more TCR recognition domains that bind specifically to the variable region of the TCR on target cells;   b) the affinity of the first biomolecular interaction domain of the binding pair of biomolecular interaction domains for the extracellular second biomolecular interaction domain of the binding pair of biomolecular interaction domains;   c) the affinity of the one or more TCR recognition domains that bind specifically to the variable region of the TCR on target cells; or   d) the expression level of the extracellular second biomolecular interaction domain of the binding pair of biomolecular interaction domains.   
     
     
         31 . The method of  claim 2 , wherein the population of target cells in the subject is depleted by at least about 5% to about 50% or greater characterized by an in vitro cell cytotoxicity assay. 
     
     
         32 . The method of  claim 1 , wherein the method is characterized to reduce off-target effects in the subject. 
     
     
         33 . The method of  claim 1 , wherein the TCR recognition domain is allogeneic, autologous, or xenogeneic to the engineered cell. 
     
     
         34 . The method of  claim 1 , wherein the TCR recognition domain is synthetic. 
     
     
         35 . The method of  claim 1 , wherein the TCR recognition domain comprises a MHC and a peptide, wherein the peptide is allogeneic, autologous, or xenogeneic to the engineered cell. 
     
     
         36 . The method of  claim 1 , wherein the TCR recognition domain comprises a MHC and a peptide, wherein the MHC or the peptide is synthetic. 
     
     
         37 . The method of  claim 1 , wherein the engineered cell further comprises a TCR signaling-responsive promoter operatively linked to a payload transgene. 
     
     
         38 . The method of  claim 37 , wherein the TCR signaling-responsive promoter is a NFAT-sensitive promoter. 
     
     
         39 . The method of  claim 1 ,
 a) wherein the binding pair of biomolecular interaction domains are collectively a pair of leucine zippers;   b) wherein the binding pair of biomolecular interaction domains are collectively a BZip (RR) and a AZip (EE);   c) wherein the binding pair of biomolecular interaction domains is a PSD95-Dlg1-zo-1 (PDZ) domain;   d) wherein the binding pair of biomolecular interaction domains are collectively a streptavidin and a streptavidin binding protein (SBP);   e) wherein the binding pair of biomolecular interaction domains are collectively a FKBP-binding domain of mTOR (FRB) and a FK506 binding protein (FKBP);   f) wherein the binding pair of biomolecular interaction domains are collectively a cyclophilin-Fas fusion protein (CyP-Fas) and a FK506 binding protein (FKBP);   g) wherein the binding pair of biomolecular interaction domains are collectively a calcineurin A (CNA) and a FK506 binding protein (FKBP);   h) wherein the binding pair of biomolecular interaction domains are collectively a gibberellin insensitive (GIA) and a gibberellin insensitive dwarf1 (GID1);   i) wherein the binding pair of biomolecular interaction domains are collectively a Snap-tag and a Halo tag;   j) wherein the binding pair of biomolecular interaction domains are collectively a T14-3-3-cdeltaC and a C-Terminal peptides of PMA2 (CT52);   k) wherein the binding pair of biomolecular interaction domains are collectively a PYL and a ABI;   l) wherein the binding pair of biomolecular interaction domains are collectively a nucleotide tag and a zinc finger domain;   m) wherein the binding pair of biomolecular interaction domains are collectively a pair of nucleotide tags;   n) wherein the binding pair of protein interaction domains are collectively a FITC and a FITC binding protein; and/or   o) wherein the binding pair of protein interaction domains are collectively a (R)-Phycoerythrin (R-PE/PE) and a R-PE/PE binding protein.   
     
     
         40 . The method of  claim 1 , wherein
 a) the binding pair of biomolecular interaction domains are collectively a nucleotide tag and a zinc finger domain and the nucleotide tag is a DNA tag or a dsDNA tag; or   b) wherein the binding pair of biomolecular interaction domains are collectively a pair of nucleotide tags and the nucleotide tags are a DNA tags or a dsDNA tags.   
     
     
         41 . The method of  claim 1 , wherein the T cell mediated inflammation or immune response is an anti-drug specific response to a biologic, cell therapy, and/or gene therapy. 
     
     
         42 . The method of  claim 1 , wherein the autoimmune disease; T cell mediated inflammation or immune response; malignant T cell condition; transplant rejection; or GvHD is prevented or treated in the subject. 
     
     
         43 . The method of  claim 1 , wherein the autoimmune disease is selected from: thyroiditis, type 1 diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, celiac disease, multiple sclerosis, Guillain-Barre syndrome, Addison's disease, and Raynaud's phenomenon, Goodpasture's disease, arthritis (rheumatoid arthritis such as acute arthritis, chronic rheumatoid arthritis, gout or gouty arthritis, acute gouty arthritis, acute immunological arthritis, chronic inflammatory arthritis, degenerative arthritis, type II collagen-induced arthritis, infectious arthritis, Lyme arthritis (e.g., post treatment Lyme disease syndrome), proliferative arthritis, psoriatic arthritis, Still's disease, vertebral arthritis, and juvenile-onset rheumatoid arthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronica primaria, reactive arthritis, and ankylosing spondylitis), palindromic arthritis, inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, guttate psoriasis, pustular psoriasis, and psoriasis of the nails, atopy including atopic diseases such as hay fever and Job's syndrome, dermatitis including contact dermatitis, chronic contact dermatitis, exfoliative dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, nummular dermatitis, seborrheic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, and atopic dermatitis, x-linked hyper IgM syndrome, allergic intraocular inflammatory diseases, urticaria such as chronic allergic urticaria and chronic idiopathic urticaria, including chronic autoimmune urticaria, myositis, polymyositis/dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma (including systemic scleroderma), sclerosis such as systemic sclerosis, multiple sclerosis (MS) such as spino-optical MS, primary progressive MS (PPMS), and relapsing remitting MS (RRMS), progressive systemic sclerosis, atherosclerosis, arteriosclerosis, sclerosis disseminata, ataxic sclerosis, neuromyelitis optica (NMO), inflammatory bowel disease (IBD) (for example, Crohn's disease, autoimmune-mediated gastrointestinal diseases, colitis such as ulcerative colitis, colitis ulcerosa, microscopic colitis, collagenous colitis, colitis polyposa, necrotizing enterocolitis, and transmural colitis, and autoimmune inflammatory bowel disease), bowel inflammation, pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, respiratory distress syndrome, including adult or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, an autoimmune hematological disorder, rheumatoid spondylitis, rheumatoid synovitis, hereditary angioedema, cranial nerve damage as in meningitis, herpes gestationis, pemphigoid gestationis, pruritis scroti, autoimmune premature ovarian failure, sudden hearing loss due to an autoimmune condition, IgE-mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis such as Rasmussen's encephalitis and limbic and/or brainstem encephalitis, uveitis, such as anterior uveitis, acute anterior uveitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, or autoimmune uveitis, glomerulonephritis (GN) with and without nephrotic syndrome such as chronic or acute glomerulonephritis such as primary GN, immune-mediated GN, membranous GN (membranous nephropathy), idiopathic membranous GN or idiopathic membranous nephropathy, membrano- or membranous proliferative GN (MPGN), including Type I and Type II, and rapidly progressive GN, proliferative nephritis, autoimmune polyglandular endocrine failure, balanitis including balanitis circumscripta plasmacellularis, balanoposthitis, erythema annulare centrifugum, erythema dyschromicum perstans, eythema multiform, granuloma annulare, lichen nitidus, lichen sclerosus et atrophicus, lichen simplex chronicus, lichen spinulosus, lichen planus, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant keratosis, pyoderma gangrenosum, allergic conditions and responses, allergic reaction, eczema including allergic or atopic eczema, asteatotic eczema, dyshidrotic eczema, and vesicular palmoplantar eczema, asthma such as asthma bronchiale, bronchial asthma, and auto-immune asthma, conditions involving infiltration of T cells and chronic inflammatory responses, immune reactions against foreign antigens such as fetal A-B-O blood groups during pregnancy, chronic pulmonary inflammatory disease, autoimmune myocarditis, leukocyte adhesion deficiency, lupus, including lupus nephritis, lupus cerebritis, pediatric lupus, non-renal lupus, extra-renal lupus, discoid lupus and discoid lupus erythematosus, alopecia lupus, systemic lupus erythematosus (SLE) such as cutaneous SLE or subacute cutaneous SLE, neonatal lupus syndrome (NLE), and lupus erythematosus disseminatus, juvenile onset (Type I) diabetes mellitus, including pediatric insulin-dependent diabetes mellitus (IDDM), adult onset diabetes mellitus (Type II diabetes), autoimmune diabetes, idiopathic diabetes insipidus, diabetic retinopathy, diabetic nephropathy, diabetic large-artery disorder, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, sarcoidosis, granulomatosis including lymphomatoid granulomatosis, Wegener's granulomatosis, agranulocytosis, vasculitides, including vasculitis, large-vessel vasculitis (including polymyalgia rheumatica and giant-cell (Takayasu's) arteritis), medium-vessel vasculitis (including Kawasaki's disease and polyarteritis nodosa/periarteritis nodosa), microscopic polyarteritis, immunovasculitis, CNS vasculitis, cutaneous vasculitis, hypersensitivity vasculitis, necrotizing vasculitis such as systemic necrotizing vasculitis, and ANCA-associated vasculitis, such as Churg-Strauss vasculitis or syndrome (CSS) and ANCA-associated small-vessel vasculitis, temporal arteritis, autoimmune aplastic anemia, Coombs positive anemia, Diamond Blackfan anemia, hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia (anemia perniciosa), Addison's disease, pure red cell anemia or aplasia (PRCA), Factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, CNS inflammatory disorders, multiple organ injury syndrome such as those secondary to septicemia, trauma or hemorrhage, antigen-antibody complex-mediated diseases, anti-glomerular basement membrane disease, anti-phospholipid antibody syndrome, allergic neuritis, Behcet's disease/syndrome, Castleman's syndrome, Goodpasture's syndrome, Reynaud's syndrome, Sjogren's syndrome, Stevens-Johnson syndrome, pemphigoid such as pemphigoid bullous and skin pemphigoid, pemphigus (including pemphigus vulgaris, pemphigus foliaceus, pemphigus mucus-membrane pemphigoid, and pemphigus erythematosus), autoimmune polyendocrinopathies, Reiter's disease or syndrome, an immune complex disorder such as immune complex nephritis, antibody-mediated nephritis, polyneuropathies, chronic neuropathy such as IgM polyneuropathies or IgM-mediated neuropathy, and autoimmune or immune-mediated thrombocytopenia such as idiopathic thrombocytopenic purpura (ITP) including chronic or acute ITP, scleritis such as idiopathic cerato-scleritis, episcleritis, autoimmune disease of the testis and ovary including autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, autoimmune endocrine diseases including thyroiditis such as autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis), or subacute thyroiditis, idiopathic hypothyroidism, Grave's disease, polyglandular syndromes such as autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), paraneoplastic syndromes, including neurologic paraneoplastic syndromes such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man or stiff-person syndrome, encephalomyelitis such as allergic encephalomyelitis or encephalomyelitis allergica and experimental allergic encephalomyelitis (EAE), myasthenia gravis such as thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan's syndrome, autoimmune hepatitis, lupoid hepatitis, giant-cell hepatitis, autoimmune chronic active hepatitis, lymphoid interstitial pneumonitis (LIP), bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, acute febrile neutrophilic dermatosis, subcorneal pustular dermatosis, transient acantholytic dermatosis, cirrhosis such as primary biliary cirrhosis and pneumonocirrhosis, autoimmune enteropathy syndrome, Celiac or Coeliac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia, amylotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear disease such as autoimmune inner ear disease (AIED), autoimmune hearing loss, polychondritis such as refractory or relapsed or relapsing polychondritis, pulmonary alveolar proteinosis, Cogan's syndrome/nonsyphilitic interstitial keratitis, Bell's palsy, Sweet's disease/syndrome, rosacea autoimmune, zoster-associated pain, amyloidosis, a non-cancerous lymphocytosis, a primary lymphocytosis, which includes monoclonal B cell lymphocytosis (e.g., benign monoclonal gammopathy and monoclonal gammopathy of undetermined significance, MGUS), peripheral neuropathy, paraneoplastic syndrome, channelopathies including channelopathies of the CNS, autism, inflammatory myopathy, focal or segmental or focal segmental glomerulosclerosis (FSGS), endocrine opthalmopathy, uveoretinitis, chorioretinitis, autoimmune hepatological disorder, fibromyalgia, multiple endocrine failure, Schmidt's syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases and chronic inflammatory demyelinating polyneuropathy, Dressler's syndrome, alopecia areata, alopecia totalis, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), male and female autoimmune infertility, e.g., due to anti-spermatozoan antibodies, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent abortion, farmer's lung, erythema multiforme, post-cardiotomy syndrome, Cushing's syndrome, bird-fancier's lung, allergic granulomatous angiitis, benign lymphocytic angiitis, Alport's syndrome, alveolitis such as allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reaction, Sampter's syndrome, Caplan's syndrome, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial lung fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endophthalmitis, erythema elevatum et diutinum, erythroblastosis fetalis, eosinophilic faciitis, Shulman's syndrome, Felty's syndrome, cyclitis such as chronic cyclitis, heterochronic cyclitis, iridocyclitis (acute or chronic), or Fuch's cyclitis, Henoch-Schonlein purpura, SCID, sepsis, endotoxemia, post-vaccination syndromes, Evan's syndrome, autoimmune gonadal failure, Sydenham's chorea, post-streptococcal nephritis, thromboangitis ubiterans, thyrotoxicosis, tabes dorsalis, chorioiditis, giant-cell polymyalgia, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemia-reperfusion injury, transplant organ reperfusion, retinal autoimmunity, aphthae, aphthous stomatitis, arteriosclerotic disorders, aspermiogenesis, autoimmune hemolysis, Boeck's disease, enteritis allergica, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, Hamman-Rich's disease, sensoneural hearing loss, ileitis regionalis, leucopenia, transverse myelitis, primary idiopathic myxedema, ophthalmia symphatica, polyradiculitis acuta, pyoderma gangrenosum, acquired spenic atrophy, vitiligo, toxic-shock syndrome, conditions involving infiltration of T cells, leukocyte-adhesion deficiency, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, diseases involving leukocyte diapedesis, multiple organ injury syndrome, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathies, oophoritis, primary myxedema, autoimmune atrophic gastritis, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine failure, autoimmune polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), myocarditis, nephrotic syndrome, primary sclerosing cholangitis, acute or chronic sinusitis, ethmoid, frontal, maxillary, or sphenoid sinusitis, an eosinophil-related disorder such as eosinophilia, pulmonary infiltration eosinophilia, eosinophilia-myalgia syndrome, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, granulomas containing eosinophils, seronegative spondyloarthritides, polyendocrine autoimmune disease, sclerosing cholangitis, sclera, episclera, Bruton's syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, ataxia telangiectasia syndrome, angiectasis, autoimmune disorders associated with collagen disease, rheumatism, allergic hypersensitivity disorders, glomerulonephritides, reperfusion injury, ischemic re-perfusion disorder, lymphomatous tracheobronchitis, inflammatory dermatoses, dermatoses with acute inflammatory components, or autoimmune uveoretinitis (AUR). 
     
     
         44 . The method of  claim 1 , wherein the method is characterized in that it exhibits cell killing activity against a population of the target cells expressing the variable region of the TCR. 
     
     
         45 . A composition comprising
 a) a soluble extracellular molecule or a soluble extracellular complex comprising:
 one or more TCR recognition domains selected to bind specifically to a variable region of a TCR on target cells, and 
 a first biomolecular interaction domain of a binding pair of biomolecular interaction domains; and 
   b) an engineered cell expressing or comprising an engineered signaling polypeptide comprising:
 an extracellular second biomolecular interaction domain of the binding pair of biomolecular interaction domains, and 
 an intracellular signaling domain. 
   
     
     
         46 . A composition comprising
 i) a soluble extracellular molecule or a soluble extracellular complex comprising:
 one or more TCR recognition domains selected to bind specifically to a variable region of a TCR on target cells, and 
 a first biomolecular interaction domain of a binding pair of biomolecular interaction domains; and 
   ii) an engineered cell expressing or comprising an engineered signaling polypeptide comprising:
 an extracellular second biomolecular interaction domain of the binding pair of biomolecular interaction domains, and 
 an intracellular signaling domain, 
   wherein the TCR recognition domain comprises sequences with at least 80% or at least 95% sequence identity to:
 a) SEQ ID NO: 18, 19, and one of 20-22; HLA-A*-0201 and SEQ ID NO: 2018; HLA-A*0301 and SEQ ID NO: 2019; HLA-A*2404 and SEQ ID NO: 2020; HLA-A*0101 and SEQ ID NO: 2021; A*01:01 and at least one of SEQ ID NOs: 2086, 2087, and 2100; A*02:01 and at least one of SEQ ID NOs: 2145, 2146, 2168, 2303, and 2312; A*24:02 and SEQ ID NO: 2517; or B*07:02 and SEQ ID NO: 2556; 
 b) HLA-A*-0101 and at least one of SEQ ID NOs: 2034-2037; HLA-A*0201 and at least one of SEQ ID NOs: 2035-2037; HLA-B*0702 and SEQ ID NO: 2038; HLA-B*0801 and SEQ ID NO: 2039; or HLA-A*-02:01 and at least one of SEQ ID NO: 2022-2024; 
 c) HLA-A*-0201 and SEQ ID NO: 2017; A*01:01 and at least one of SEQ ID NOs: 2084 and 2085; or A*02:01 and SEQ ID NO: 2271; 
 d) DRB1*04:01 and SEQ ID NO: 2027; or A*02:01 and SEQ ID NO: 2126; 
 e) A*02:01 and SEQ ID NO: 2125; 
 f) HLA-A*0201 and at least one of SEQ ID NO: 2040-2048, 2068, and 2069; HLA-A*0301 and at least one of SEQ ID NO: 2049 a; HLA-A*1101 and at least one of SEQ ID NOs: 2050 and 2051; HLA-A*2402 and at least one of SEQ ID NOs: 2052-2053; HLA-A*2902 and SEQ ID NO: 2054; HLA-B*0702 and at least one of SEQ ID NOs: 2055-2057; HLA-B*0801 and at least one of SEQ ID NOs: 2058 and 2059; HLA-B*3501 and at least one of SEQ ID NOs: 2060-2066; or HLA-A*0101 and SEQ ID NO: 2067; 
 g) HLA-A*0301 and SEQ ID NO: 2070; HLA-A*2301 and SEQ ID NO: 2071; HLA-A*2402 and at least one of SEQ ID NOs: 2071-2073; HLA-B*0801 and at least one of SEQ ID NOs: 2076-2079; HLA-B*3501 and at least one of SEQ ID NOs: 2080 and 2081; or A*01:01 and at least one of SEQ ID NOs: 2101 and 2102; 
 h) A*01:01 and at least one of SEQ ID NOs: 2082, 2083 and 2088; or A*0201 and SEQ ID NO: 2112; 
 i) A*01:01 and SEQ ID NO: 2089; 
 j) A*01:01 and SEQ ID NO: 2098; 
 k) A*01:01 and SEQ ID NO: 2106; 
 l) A*01:01 and at least one of SEQ ID NOs: 2107 and 2108; 
 m) A*0201 and SEQ ID NO: 2123; 
 n) A*02:01 and SEQ ID NO: 2132; 
 o) A*02:01 and SEQ ID NO: 2136; 
 p) A*02:01 and SEQ ID NO: 2157; 
 q) A*02:01 and SEQ ID NO: 2158; 
 r) A*02:01 and SEQ ID NO: 2165; 
 s) A*02:01 and SEQ ID NO: 2167; 
 t) A*02:01 and SEQ ID NO: 2282; or 
 u) A*02:01 and SEQ ID NO: 2284. 
   
     
     
         47 . A composition comprising a soluble extracellular molecule or a soluble extracellular complex comprising:
 a TCR recognition domain that binds specifically to a variable region of a TCR on a target cell, and   a first biomolecular interaction domain of a binding pair of biomolecular interaction domains.