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PubMed2024

Targeting peptide antigens using a multiallelic MHC I-binding system.

Identifying highly specific T cell receptors (TCRs) or antibodies against epitopic peptides presented by class I major histocompatibility complex (MHC I) proteins remains a bottleneck in the development of targeted therapeutics. Here, we introduce targeted recognition of antigen-MHC complex reporter for MHC I (TRACeR-I), a generalizable platform for targeting peptides on polymorphic HLA-A*, HLA-B* and HLA-C* allotypes while overcoming the cross-reactivity challenges of TCRs. Our TRACeR-MHC I co-crystal structure reveals a unique antigen recognition mechanism, with TRACeR forming extensive contacts across the entire peptide length to confer single-residue specificity at the accessible positions. We demonstrate rapid screening of TRACeR-I against a panel of disease-relevant HLAs with peptides derived from human viruses (human immunodeficiency virus, Epstein-Barr virus and severe acute respiratory syndrome coronavirus 2), and oncoproteins (Kirsten rat sarcoma virus, paired-like homeobox 2b and New York esophageal squamous cell carcinoma 1). TRACeR-based bispecific T cell engagers and chimeric antigen receptor T cells exhibit on-target killing of tumor cells with high efficacy in the low nanomolar range. Our platform empowers the development of broadly applicable MHC I-targeting molecules for research, diagnostic and therapeutic applications.

Humans↗
PubMed2025

Substitution of Glutamic Acid at Position 71 of DRβ1*04:01 and Collagen-Specific Tolerance Without Alloreactivity.

OBJECTIVE: The DRB1 locus is strongly associated with both susceptibility and resistance to rheumatoid arthritis (RA). DRB1 alleles encoding the VKA or VRA epitope in positions 11, 71, and 74 confer the highest risk of developing RA, whereas the allele encoding VEA is protective. We therefore investigated the feasibility of creating antigen-specific tolerance without inducing alloreactivity by replacing lysine with glutamic acid at position 71 in DRβ1*04:01. METHODS: Individual DRB1 alleles and the DRB1*04:01K71E allele were cloned into T2 cell lines to measure binding of biotinylated peptides. Transgenic animals expressing DRB1*04:01, DRB1*01:01, or DRB1*04:01K71E were injected with collagen to measure T cell proliferation. Skin and bone marrow transplants between DRB1*04:01K71E and DRB1*04:01 mice were performed to determine if the single amino acid change at position 71 would be recognized as foreign. DRB1*04:01 mice transplanted with DRB1*04:01K71E bone marrow were injected with collagen to test if resistance to collagen sensitization could be transferred. RESULTS: Replacing lysine (K) at position 71 in DRβ1*04:01 with glutamic acid (E) blocked collagen peptide binding and rendered the DRB1*04:01K71E mice resistant to collagen sensitization. Skin and bone marrow transplants from DRB1*04:01K71E mice were not rejected by DRB1*04:01 mice, suggesting the single E71 difference was not recognized as allogeneic. Bone marrow from DRB1*04:01K71E mice adoptively transferred antigen-specific tolerance to collagen to DRB1*04:01 mice. CONCLUSION: These studies demonstrate that editing a single amino acid in DRβ1*04:01 blocks collagen peptide binding without inducing alloreactivity and could therefore represent a gene therapy approach to induce antigen-specific passive tolerance.

Animals↗
PubMed2026

A modular γδ TCR-T platform combining KRAS pMHC targeting with re-dosable mRNA engager redirection.

Solid tumors often evade TCR-engineered αβ T cells when antigen expression varies or when the restricting Human Leukocyte Antigen (HLA) allele is lost. γδ T cells, in contrast, detect cellular dysregulation through non-peptide/Major Histocompatibility Complex (MHC) cues, including phosphoantigens and stress ligands, and can be developed as allogeneic therapies. Although intratumoral γδ T cell signatures are associated with improved outcome across cancers, γδ recognition itself is broad and still selected within the thymus just as αβ T cell receptors (TCRs) are. It does not, however, anchor specificity to a defined driver-mutation pMHC epitope. We therefore asked whether a high-affinity, co-receptor-independent αβ TCR could graft oncogenic-driver specificity onto γδ T cells while leaving the endogenous γδ TCR intact. We knocked the KRASG12V/HLA-A*11:01 TCR A11v into primary human γδ T cells. Engineered cells co-expressed the transgenic αβ TCR and the endogenous γδ TCR and lysed KRASG12V/HLA-A*11:01+ tumor cells in vitro and in vivo. To cover potential resistance through loss of HLA-A*11:01, we delivered an mRNA lipid nanoparticle (LNP) encoding a secreted mesothelin×CD3 (M5) bispecific T cell engager (TCE). LNP-M5 produced circulating TCE that redirected γδ A11v T cells and polyclonal bystander T cells to kill mesothelin+ targets, accompanied by development of higher γδ A11v T cell counts in vivo. In humanized mice bearing mixed HLA-A*11:01+ and HLA-A*11:01 - KRASG12V tumors, γδ A11v T cells produced transient control, whereas adding LNP-M5 yielded complete responses and prolonged survival. Thus, this two-part therapy couples invariant driver targeting to tunable redirection and addresses loss of the restricting HLA allele, a central escape route for TCR-based therapy. It provides an off-the-shelf reagent to enable KRAS-anchored treatment with the ability to redeliver the reagent.

Humans↗
PubMedDate not supplied

Nature of cold-reactive antibodies to lymphocyte surface determinants in systemic lupus erythematosus.

Antilymphocyte antibodies in serum from patients with systemic lupus erythematosus (SLE), as detected by microcytotoxicity and indirect immunofluorescence, were predominantly cold reactive and of the IgM class. These IgM antibodies were most active at 4 degrees C. IgG antibodies were infrequent, and were only minimally lymphocytotoxic. Most sera were cytotoxic for autologous lymphocytes and were equally reactive with normal and SLE lymphocytes, as well as with B- and T-cell preparations. Separate T- and B-cell specificities, which appeared not to be related to HL-A determinants, were identified by differential absorption experiments. The functional significance of these antilymphocyte antibodies is discussed.

Animals↗
PubMed1975

[The lymphocyte cytotoxicity test in tumor immunology (author's transl)].

The cytotoxic action of lymphocytes on cancer cells in vitro indicates sensitization of the patient against his own tumor. The technical difficulities of this test and possibilities of standardization and simplifying the procedure are discussed. Critical steps are isolation of lymphocytes and culturing target cells without loosing their specific antigenic structure. The need for specificity controls both for lymphocytes and tumor cells is emphasized. Labelling tumor cells with isotopes represents a major improvement in evaluating the result. The role of thymus- and bone marrow-dependent lymphocytes as well as blocking factors in the serum of tumor patients can be analyzed in the cytotoxic assay. A better understanding of these mechanisms may facilitate a therapeutic approach by manipulating the interaction of tumor cells and host.

Animals↗
PubMed1975

Differences in the surface proteins of mouse B and T cells.

We have selectively labeled the surface of mouse thymus-dependent (T) and thymus-independent (B) lymphocytes by means of lactoperoxidase-catalyzed iodination. Examination of the labeled proteins by electrophoresis in the presence of sodium dodecylsulfate followed by autoradiography revealed differences in the cell surface proteins of B and T cells. Proteins from labeled thymocytes, T cell lymphomas, and both normal and activated peripheral T cells give a broad band of radioactivity corresponding to at least two protein components with apparent molecular weights of 170,000 to 190,000. This band is absent from autoradiographs of iodinated B cell proteins, which instead have another band corresponding to a protein with an apparent molecular weight of about 220,000. We have shown that these T and B cell marker proteins are synthesized by the cell and are not serum components selectively bound to the cell surface. We have also established that these proteins are the major iodinated species precipitated from Nonidet P-40 cell lysates by rabbit anti-mouse lymphocyte serum, suggesting that they are the major antigens recognized by rabbit antibodies to mouse lymphocytes.

Animals↗
PubMed2025

Cancer-testis antigen ACRBP: Cytotoxic response to its HLA-A2 restricted peptide and immune features in ovarian cancer.

While our prior study identified the HLA-A *0201-restricted ACRBP epitope peptide and demonstrated its capacity to generate cytotoxic T lymphocytes (CTLs) in vitro, the clinical relevance of the peptide-induced T cell reactivity in ovarian cancer (OC) patients and the in vivo anti-tumor efficacy of these CTLs remain unexplored. In this study, dendritic cells were sensitized with ACRBP peptide (ALLVLCYSI) and co-cultured with autologous CD8+T cells to induce the production of specific cytotoxic T lymphocytes (Pep-CTLs). The anti-tumor effects of Pep-CTLs were evaluated in SCID mice bearing human ovarian cancer (OC) OVCAR-3 cells. Concurrently, we co-cultured ALLVLCYSI peptide with peripheral blood mononuclear cells (PBMCs) from OC patients (HLA-A2+, ACRBP+) and assessed the number of specific T cells using ELISPOT assays. The immunological impact of the ACRBP peptide against human OC was validated through both in vitro and in vivo experiments. These findings establish a preclinical foundationfor developing ACRBP peptide-based vaccines in OC immunotherapy. To further elucidate ACRBP's role in OC treatment, the study analyzed single-cell RNA sequencing data from 8 OC patients and bulk RNA sequencing data from the Cancer Genome Atlas Project (TCGA) comprising 308 ovarian cancer cases. This analysis aimed to explore the heterogeneity among ACRBP-expressing tumor cell populations and to investigate the correlation between ACRBP expression and immune molecule expression (including MHC and chemokines) alongside chemotherapy response. These insights furnish a theoretical framework supporting the future application of ACRBP in tumor immunotherapy and strategies to prevent immune escape.

Humans↗
PubMed1975

Tolerance to histocompatibility determinants in tetraparental bone marrow chimeras.

Tetraparental bone marrow chimeras were produced by injecting lethally X-irradiated F1 hybrids with relatively high numbers of T-cell-depleted bone marrow cells from both allogeneic parental strains. The mice survival in excellent health and showed a stable, approximately 50:50 (parent:parent), lymphoid cell chimerism lasting for at least 7 mo after irradiation; regeneration of host-type hemopoietic cells was very limited. Thymus, lymph node, and thoracic duct lymphocytes showed specific unresponsiveness to host mixed leukocyte reaction (MLR) determinants. Similarly specific tolerance to H-2 antigens of host type was demonstrated in spleen and lymph node. No suppressor cells could be demonstrated in either system and blocking serum factors could not be found. The results suggest specific deletion of functional T cells reactive to host-type MLR and cell-mediated lympholysis determinants.

Animals↗
PubMed1975

Antibody response in C3H mice injected with CBA lymphoid cells as detected by membrane immunofluorescent staining.

Lymphocytes from CBA mice are strongly responsive to cells from the H-2-identical strain C3H in vitro (MLC), whereas C3H lymphocytes are poorly reactive against CBA cells. Immunization of CBA mice with C3H lymphocytes did not yield any detectable specific antibodies. On the other hand, C3H mice immunized with CBA cells produced specific antibodies as detected by membrane immunofluorescence. Mice of the strains AKR and DBA/2 also possess this specific membrane alloantigen. We thus conclude that it is now possible to discriminate among lymphocytes of CBA and C3H origin.

Animals↗
PubMed1975

Normal and altered phenotypic expression of immunoglobulin genes.

Genetically controlled intraspecific differences between immunoglobulins (allotypes) provide valuable markers for the study of the quantitative expression of allelic and nonallelic alternative forms of immunoglobulins (Igs) during the normal development of rabbits. Heterozygous rabbits are mosaics of cells expressing different Ig-genes since fully differentiated productive cells generally secrete only one of alternative forms of Ig. The proportions of cells that differentiate to produce allelic forms of immunoglobulins during normal development depend on the particular heterozygous genotype. The normal proportions of some markers can be drastically altered if the differentiation of lymphoid cells in the young rabbit occurs in the milieu of antibody specific for one form (allotype suppression). An initiating step in the establishment of persistent allotype suppression is probably the interaction of antiallotype antibody with allotype-bearing receptors on lymphoid cell surfaces, but the mechanism for the maintenance of a state of chronic suppression may well be more complex. Allotype suppression can be viewed as one example of numerous immunological phenomena that reflect specific and finely tuned regulatory mechanisms governing the differentiation and clonal expansion of lymphoid cells destined to secrete immunoglobulins.

Alleles↗
PubMed1975

Identification of lymphoid cells in cultured of murine leukocytes and thymus.

Several culture conditions and media were studied in an effort to establish long-term cultures of murine lymphoid cells from blood and thymus. Cultures vessels included small glass bottles and rubber-stoppered tubes. Media such as Roswell Park Memorial Institute 1640, 1700, 1701, 1715, GEM 1717, NCTC, fetal calf and horse serum supplements, and conditioned medium were tried. Lymphoid cells in mouse leukocyte cultures survived as long as eight months before dying out. However, lymphoid cells in thymus cell cultures, strarted and maintained with GEM 1717 medium with 20% fetal calf serum supplementation, gave rise to cell lines that continued to yield subcultures for more than 2 years. Mcroscopic examination of thymus cell subcultures revealed lymphoid and thymic epighelioid cells. Tumorigenicity studies of one cell line were negative. Chromosomal preparations of this cell line often contained near-normal karyotypes but were complicated by the presence of binucleated cells. Live cell fluorescent antibody assays for surface theta-antigen and immunoglobulin revealed immunoglobulin-negative cells possessing barely detectable theta determinants. Functional assays for thymus-derived lymphoid cell activity suggested that these cells were mitogen responsive and weakly reactive in one-way mixed lymphocyte culture. On the basis of this evidence it was sugguested that these cells represent a class of T-cells (thymus-derived lymphocytes) that have all but lost theta antigen, possibly due to prolonged culture.

Animals↗
PubMed1975

Immunofluorescent studies on antibodies directed to a buried membrane structure present in lymphocytes and erythrocytes.

Brief digestion of human peripheral blood lymphocytes by vibrio cholera neuraminidase (VCN) revealed hidden components of the membrane. Autologous human serums contained antibodies directed to these components that were readily demonstrated by immunofluorescence. Antibodies of similar specificity were found in all normal serums. The antibodies were principally of the IgM variety with lesser amounts of the IgG class present. They were equally active at 4 degrees C and 37 degrees C. The VCN revealed membrane determinants were present in normal B and T lymphocytes, monocytes, lymphocytes of patients with chronic lymphatic leukemia and cells of lymphoid lines. The newly revealed determinants slowly disappeared upon culture of the lymphocytes. These hidden components were similarly demonstrated in erythrocyte membranes and represent the T antigen long known for the red blood cells. Absorption by either VCN treated autologous lymphocytes or erythroyctes removed all of the antibodies capable of reacting with both cell types. Absorption by VCN digested isologous lymphocytes removed all reactivity with autologous lymphocytes.

Absorption↗
PubMed1975

Detection of membrane-associated antigens on lymphoid cells by antibody coupled to staphylococcal protein A.

A simple technique is described for the detection of membrane-associated antigens on lymphoid cells. It is based on the observation that the protein A component of staphylococci binds to the Fc pieces of IgG molecules. Lymphocytes from various sources (mouse, rat, and human tissues) were incubated with hyperimmune antisera directed against surface determinants. Subsequent treatment with a suspension of staphylococci containing protein A permitted visualization of both the presence and distribution of determinants on the cell membrane. The method had comparable sensitivity to the fluorescent sandwich technique and could be used to detect a variety of membrane antigens on both T cells and B cells.

Animals↗