Research

Our Research

Decoding immune specificity

Our goal is to uncover the fundamental principles governing complex immune responses. By integrating systems biology with biomolecular design, we build technologies to systematically dissect and reconstruct these systems. This engineering-first approach allows us to directly decode immune specificity in patient-derived samples across diverse diseases. Ultimately, we aim to translate these mechanistic insights into effective immunomodulatory therapies for autoimmunity, cancer, and infectious diseases.

TScan platform for genome-scale T-cell antigen discovery

01 · Technology

Engineering Technologies to Decode T Cell Specificity

Despite major advances in T-cell immunology, the comprehensive landscape of cognate antigens—and the molecular logic that enforces self–non-self discrimination—remains largely unresolved. Conventional assays survey only narrow, pre-selected antigen panels, capturing a small fraction of T-cell specificity. To overcome this limitation, we engineered genome-scale, high-throughput discovery platforms that tile the entire human peptidome and virome. These unbiased libraries, coupled to sensitive functional reporters, now permit systematic identification of antigens recognized by both CD8⁺ and CD4⁺ T cells.

Explore the platforms

TScan-I

A genome-scale platform for identifying cognate antigens recognized by CD8⁺ T cells across the human proteome.

TScan-II

A genome- and virome-scale platform for de novo discovery of peptide–HLA class II antigens recognized by CD4⁺ T cells.

We continue to expand these platforms to resolve T-cell recognition with greater molecular precision and accelerate the development of vaccines and antigen-directed immunotherapies.

Molecular mechanisms governing immune tolerance

02 · Autoimmunity

Molecular Triggers of Immune Tolerance Failure

Identifying the earliest molecular events that trigger the loss of immune tolerance is inherently difficult: most autoimmune diseases are diagnosed only after substantial, chronic tissue damage, while conventional candidate-based screens capture only a fraction of the relevant antigens. Immune-checkpoint inhibitors provide a rare window into these early events. By blocking inhibitory receptors such as CTLA-4 and PD-1/PD-L1, these therapies can provoke rapid-onset immune-related adverse events, effectively modeling acute tolerance failure in real time.

Questions we are asking

Leveraging our genome-scale TScan-I and TScan-II platforms, we can now pinpoint the antigens that ignite autoreactive T-cell responses in both classical autoimmune disease and checkpoint inhibitor–induced adverse events.

Homeostatic Regulation

Which peptide–HLA interactions sustain regulatory T-cell function and systemic tolerance in healthy tissues?

Drivers of Pathology

What specific antigens or signaling pathways are indispensable for initiating pathogenic effector T-cell activity once tolerance is breached?

Comparative Immunopathogenesis

How do the molecular circuits underlying immune-related adverse events align with or diverge from those operating in spontaneous autoimmune disease?

By capturing the antigens that trigger pathologic T-cell activity at the moment tolerance fractures, we can move beyond cataloguing reactive epitopes toward predictive, quantitative models of immune equilibrium. These models may expose shared molecular fault lines across autoimmune syndromes, explain tissue-specific vulnerabilities under checkpoint blockade, and reveal druggable nodes that can be tuned without broadly suppressing protective immunity.

Tumor-reactive T cells and antigen-specific immune responses

03 · Cancer

The Antigenic Lexicon of Tumor-Reactive T Cells

Cancer immunotherapy harnesses the immune system’s ability to recognize and eliminate tumor cells, largely through antigen-specific T cells. Despite major clinical advances, patient responses remain highly variable. Although single-cell studies have defined diverse T-cell states within the tumor microenvironment, the antigens that give rise to those states—and determine their functional consequences—remain poorly understood.

Questions we are asking

By combining TScan with single-cell profiling, we can directly connect the functional state of a tumor-infiltrating T cell to the antigen it recognizes.

Antigen-Specific Shaping of T-Cell States

Which tumor-derived antigens—including neoantigens, self-peptides, and latent or oncoviral epitopes—drive the emergence of progenitor-exhausted, terminally exhausted, tissue-resident, or regulatory T-cell states?

Functional Consequences of Antigen Class

How does recognition of self, neoantigen, or viral epitopes relate to productive tumor control, immune dysfunction, and resistance to immunotherapy?

Predictive and Therapeutic Implications

Can antigen-resolved T-cell signatures predict clinical outcomes, and can newly identified epitopes guide the development of personalized vaccines or adoptive T-cell therapies?

By integrating antigen discovery with single-cell functional and transcriptomic profiling, we aim to construct an antigen-resolved view of the tumor immune response. This work will define how antigen specificity shapes T-cell behavior, reveal mechanisms of immune evasion, and identify predictive biomarkers and therapeutic targets for more precise cancer immunotherapies.

Support

Funding & Support

Work in the Haj-Dezfulian Lab is generously funded by: