Research ArticleT CELLS

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

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Science Immunology  26 Feb 2021:
Vol. 6, Issue 56, eabe1801
DOI: 10.1126/sciimmunol.abe1801

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Co-opting erythrocyte clearance

While T cell dysfunction contributes to immune evasion in cancer and chronic viral infection, strategies that induce dysfunction in autoreactive T cells may facilitate self-tolerance. Watkins et al. used phage display to identify a human antibody fragment (Fab) that selectively binds erythrocytes, enabling efficient antigen targeting to splenic antigen-presenting cells that rapidly clear apoptotic erythrocytes. Fab-tethered antigen induced antigen-specific T cell dysfunction in mice that was sustained in response to antigen rechallenge for at least 3 months and required Batf3-dependent dendritic cells. In a murine model of experimental autoimmune encephalomyelitis, erythrocyte-targeted antigen prevented encephalogenic T cells from contributing to autoimmune pathology, demonstrating the therapeutic potential of leveraging erythrocyte clearance pathways to disarm overactive T cells.


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.

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