BME Faculty Member Search- Stephanie Gaglione- Decoding and engineering T cell recognition at scale

T cells respond to specific antigens in cancer, infection, and autoimmunity, yet these interactions remain among the least predictable in biology. Decoding this specificity is key to designing targeted immunotherapies, but existing technologies cannot link the vast diversity of T cell receptors (TCRs) and antigens. Addressing this major challenge, I introduce tools to sensitively map TCRs to antigens at scale and apply them to pinpoint disease-relevant T cells in autoimmunity and cancer. Sequencing of patient samples generates large-scale data on immune receptor sequences and cell states but little information on antigen specificity. I developed an inexpensive approach to reconstruct TCRs from sequence data alone and functionally test them against hundreds of antigens simultaneously. Using this pipeline, I precisely identified autoreactive T cells in vitiligo and found transcriptomic signatures similar to skin-reactive T cells in melanoma. Extending this work, I developed a platform capable of even larger screens—millions of TCRs against hundreds of antigens at once. My research group will build on these tools to decode and reprogram antigen-specific T cells, engineering the next generation of targeted immunotherapies.