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Deciphering the regulatory T cell repertoire: towards biomarkers and biotherapies for autoimmune diseases

Final Report Summary - TRIPOD (Deciphering the regulatory T cell repertoire: towards biomarkers and biotherapies for autoimmune diseases)

Regulatory T cells (Tregs) are essential to maintaining immune system homeostasis, controlling inflammation, and protecting us from autoimmune diseases. Like all T cells, Tregs are equipped with an antigen-specific receptor (T cell receptor, TCR) that recognizes antigens. These receptors are generated by somatic rearrangements of the multiple TCR genes, a process which has the potential to produce over 1020 different TCRs. Each T cell harbors a single TCR and the collection of TCRs from a T cell population defines its TCR repertoire. In a given individual, the overall TCR repertoire is estimated to comprise approximately 108 different TCRs. TCRs are supposed to provide the specificity of the T cell response by binding to specific peptides, thereby participating in the process of T cell activation and function.
How evolution shaped a process that generates TCRs that respond efficiently to peptides that are not yet present, i.e. from an infectious agent to come, is a central question of immunology. The paradigm is that the selection of a diverse enough repertoire of TCRs should always provide a proper, though rare, specificity for any given need. Expansion of such rare T cells would provide enough fighters for an efficacious immune response and later enough antigen-experienced cells for memory.
As Tregs express TCRs, there is a similar assumption that Tregs are likely specific for self-antigens. We thus started our project with the aim of understanding the TCR repertoire of Tregs, by comparison with the repertoire of the effector T cells that principally fight viral infection. We hypothesized that understanding the Treg repertoire would provide (i) biomarkers for autoimmune diseases (that result from a Treg insufficiency) and (ii) specific TCRs for use in cell-based Treg therapies.
Using a robust methodology for high-resolution sequencing of TCR repertoires, we made the surprising observation that some TCRs appear to have a fuzzy rather than a focused specificity. We found pleiospecific TCRs that could recognize multiple peptides from different viruses, which is a challenge to the paradigm of the specificity of antiviral immune responses.
This observation had a profound impact on the specific goals of our project.
In order to understand Treg specificities and to discover TCR-related biomarkers, rather than look for finely specific TCRs we looked for setting-specific signatures of “fuzzily specific responses.” We identified such signatures characterizing the Tregs and Teffs of type 1 diabetes patients and are currently investigating them as potential biomarkers of response to IL-2 therapy in such patients.
In designing TCR-based Treg cell therapy products, we first used polyclonal products. Likewise, we are now in the late pre-clinical development of a therapy based on IL-2 sufficient “super-Tregs” for the treatment of graft-versus-host disease after allogeneic stem cell transplantation. For settings that could benefit from targeting, like autoimmune diseases of the brain, we now favor a design based on antibody-mediated rather than TCR-mediated targeting.
In a broader vision, our results prompt reconsideration of the paradigm of a highly diverse adaptive immune repertoire driving a highly antigen-specific immune response. The immune response may instead proceed through tinkering, as evolution does. In fighting life-threatening infections, the recruitment of frequent effector T cells with fuzzy specificities might be more efficient and rapid than having to rely on the recruitment and expansion of rare cells with a stringent specificity. For Tregs that prevent immune attack against tissues, fuzzy specificities could provide a shared and larger pool of cells for the permanent maintenance of a state of tolerance to diverse tissues.
Our results have important implications for the understanding and further study of the adaptive immune response in health, diseases, and immunotherapies. Our work provides the conceptual framework needed to revisit the paradigmatic notion of specificity.