Persistent antigen exposure via the eryptotic pathway drives terminal T cell dysfunction

Abstract

Although most current treatments for autoimmunity involve broad immunosuppression, recent efforts have aimed to suppress T cells in an antigen-specific manner to minimize risk of infection. One such effort is through targeting antigen to the apoptotic pathway to increase presentation of the antigen of interest in a tolerogenic context. Erythrocytes present a rational candidate to target because of their high rate of eryptosis, which facilitates continual uptake by antigen-presenting cells in the spleen. Here, we develop an approach that binds antigens to erythrocytes to induce sustained T cell dysfunction. Transcriptomic and phenotypic analyses revealed signatures of self-tolerance and exhaustion, including up-regulation of PD-1, CTLA4, Lag3, and TOX. Antigen-specific T cells were incapable of responding to an adjuvanted antigenic challenge even months after antigen clearance. With this strategy, we prevented pathology in a mouse experimental autoimmune encephalomyelitis model. CD8+ T cell education occurred in the spleen and was dependent on cross-presenting Batf3+ dendritic cells. These results demonstrate that antigens associated with eryptotic erythrocytes induce lasting T cell dysfunction that could be protective in deactivating pathogenic T cells.

Engineered RBCs Encapsulating Antigen Induce Multi-Modal Antigen-Specific Tolerance and Protect Against Type 1 Diabetes

“…Several antigen-coupled apoptotic cell-based approaches have been previously explored to induce antigen-specific tolerance ( 50 ). These include conjugation of antigen to leukocytes by chemical methods and covalent or non-covalent linkage of antigen to RBCs ( 18 – 20 , 23 ). Chemical methods for antigen conjugation exhibit high variability in coupling efficiency and cause alterations in protein structure and activity ( 51 ).…”

Epitope-based precision immunotherapy of Type 1 diabetes

“… 79 , 80 , 94 Alternative to using nanoparticles, peptides may be grafted onto natural polymers (hyaluronic acid, to produce SAgA), 71 conjugated to glycopeptides that enhance uptake in liver 95 or to antibodies against APC surface markers 72–96 – 98 or associated with erythrocytes that are taken up by tolerogenic splenic macrophages by efferocytosis. 99 Peptides may be expressed from DNA or mRNA vaccines, which often require formulation into nanoparticles or liposomes to improve the delivery and control the biodistribution. 77 , 100 Peptides can also be provided as already presented on MHC molecules, either on the surface of tolerogenic dendritic cells 83 or on the surface of small nanoparticles, 84 the latter providing TCR stimulation without any costimulation to tolerize T cells.…”

TOX regulates T lymphocytes differentiation and its function in tumor

“…Maestre et al (8) prepared a new anti-TOX monoclonal antibody (mAb) (clone NAN448B) utilizing the HIS tag produced by the ES21 strain as an antigen and immunizing Wistar rats with TOX fusion proteins containing 250 amino acid residues. A single low dose of red blood cell-related antigen is sufficient to initiate depletion-related procedures (50), which has contributed to the development of new interventions for autoimmune diseases.…”