Assistant Professor, MIT | Core Member, Ragon Institute Ragon Inst. of MGH, MIT, and Harvard, United States
Introduction/Rationale: The ability to discriminate self from non-self is a cornerstone of adaptive immunity, enabling defense against threats while preserving host integrity. Traditionally, this decision has been attributed to molecular mechanisms acting within individual T cells. However, our recent findings reveal that self-reactive T cells are routinely activated in healthy hosts and may be integral participants in normal physiological processes—suggesting that self–non-self discrimination cannot be understood at the level of single cells alone.
Methods: We investigate how discrimination emerges as a coordinated, multicellular computation that evolves dynamically across space and time. We are particularly focused on how local networks of dendritic cells, regulatory T cells, and conventional T cells collectively determine whether an immune response becomes inflammatory, tolerogenic, or reparative. By combining high-resolution multiplexed tissue imaging, computational modeling, and in vivo perturbations, we aim to map how these multicellular interactions are organized within tissues, how they process information and compute outcomes, and how they adapt to distinct physiological environments to balance tolerance with host defense.
Results: Our ongoing studies have uncovered several key features of immune regulation across scales, including: 1) multicellular mechanisms that control T cell fate decisions, 2) local adaptations that bias these decisions according to tissue-specific constraints, 3) unexpected roles for self-reactive T cell responses in maintaining tissue physiology, and 4) organ-scale mechanisms that sharpen the boundary between self and non-self as host threats expand and resolve.
Conclusion: By redefining self–non-self discrimination as a collective process and recognizing self-reactivity as a normal facet of tissue physiology, our work seeks to uncover the design principles that enable the immune system to balance responsiveness and restraint across scales—from molecular signaling to whole-organ function.
