Abstract
New approaches based on induction of antigen-specific immunological tolerance are being explored for treatment of autoimmunity and prevention of immunity to protein drugs. Antigens associated with apoptotic debris are known to be processed tolerogenically in vivo. Our group is exploring an approach toward antigen-specific tolerization using erythrocyte-binding antigens, based on the premise that as the erythrocytes circulate, age and are cleared, the erythrocyte surface-bound antigen payload will be cleared tolerogenically along with the eryptotic debris. Here, we characterized the phenotypic signatures of CD8+ T cells undergoing tolerance in response to soluble and erythrocyte-targeted antigen. Signaling through programmed death-1/programmed death ligand-1 (PD-1/PD-L1), but not through cytotoxic T lymphocyte antigen 4 (CTLA4), was shown to be required for antigen-specific T cell deletion, anergy and expression of regulatory markers. Generation of CD25+FOXP3+ regulatory T cells in response to erythrocyte-targeted antigens but not soluble antigen at an equimolar dose was observed, and these cells were required for long-term maintenance of immune tolerance in both the CD4+ and CD8+ T cell compartments. Evidence of infectious tolerance was observed, in that tolerance to a one antigenic epitope was able to regulate responses to other epitopes in the same protein antigen.
Highlights
Shown positive outcomes in several models of autoimmunity such as T1D12 and multiple sclerosis[13], in allergy[14] and tissue transplantation[15]
As PD-1 and CTLA4 are upregulated on proliferating OTI T cells in response to erythrocyte-targeted antigens (PD-1 differentially in response to erythrocyte binding, CTLA4 not) and are commonly associated with immune tolerance[22], we evaluated the requirement of these signaling molecules for induction of antigen-specific T cell deletion, anergy and differentiation into Tregs in response to erythrocyte-targeted OVA. 106 CFSE-labeled OTI T cells were adoptively transferred on day 0
These results show that the tolerogenic effect of erythrocyte-associated antigen requires stimulation the PD-1/PD-L1 axis, and that CTLA4 contributes, to a lesser extent
Summary
Shown positive outcomes in several models of autoimmunity such as T1D12 and multiple sclerosis[13], in allergy[14] and tissue transplantation[15]. Following the idea of using apoptotic cells as a carrier for antigens to achieve tolerogenic antigen presentation, our laboratory has been exploring targeting antigen to the surface of erythrocytes via administration of a glycophorin A-binding antigen form[16]. Due to their limited life span and inability to self-repair, billions of erythrocytes die by eryptosis, a process analogous to apoptosis, every minute and are removed from blood, representing a massive population of apoptotic cells that can be targeted for induction of immune tolerance[17]. Regulatory T cells (Tregs) were induced in response to erythrocyte-associated antigen but not free antigen at equivalent dose, regulating response to antigen challenge in both the CD4+ and CD8+ T cell compartments
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