About

Stephen C. Harrison is a Professor of Biological Chemistry and Molecular Pharmacology at Harvard University. He played a central role in guiding the Harvard Biochemical Sciences Tutorial Program for decades, including serving as Head Tutor from 1972 to 1996. Harrison emphasizes that the tutorial was designed to help students learn how to think about scientific problems and how discoveries emerge from evidence, rather than just absorbing facts about biology. His contributions have helped shape the program's focus on developing scientific thinking through discussion of primary literature, fostering intellectual relationships between students and practicing scientists, and mentoring students toward research and honors projects. His work has been instrumental in maintaining the tutorial's tradition of close mentorship and engagement with emerging fields in biological sciences.

Research topics

• Biology
• Immunology
• Internal medicine
• Cell biology
• Medicine
• Virology
• Computational biology
• Genetics
• Molecular biology
• Cancer research

Selected publications

• A unified network systems approach uncovers a core novel program underlying T follicular helper cell differentiation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-24

  preprintOpen access

  T follicular helper (Tfh) cells are central to the adaptive immune response and exhibit remarkable functional diversity and plasticity. The complex nature of Tfh cell populations, inconsistent findings across experimental systems and potential differences across species have fueled ongoing debate regarding core regulatory pathways that govern Tfh differentiation. Many studies have experimentally investigated individual proteins and circuits involved in Tfh differentiation in limited contexts, each providing only a partial understanding of the process. To address this, we adopted a novel multi-scale network systems approach that incorporates both regulatory and protein-protein interactions. Our approach integrates diverse data types, captures regulation across multiple levels of immune system organization, and recapitulates known drivers. Further, we discover a core Tfh gene set that is conserved across tissue types and disease contexts, and is consistent across data modalities - bulk, single-cell and spatial. While components of this set have been individually reported, a novel aspect of our work lies in the discovery, characterization, and connectivity of this core signature using a single unbiased approach. Using this method, we also uncover a novel function of IL-12, a molecule with reported conflicting functions, in the regulation of Tfh differentiation. Notably, we find that, in both humans and mice, IL-12 is permissive for the differentiation of Tfh precursors, but blocks subsequent differentiation into GC Tfh cells. Overall, this work elucidates novel networks with unexplored roles in governing Tfh cell differentiation across species and tissues, paving the way for novel -therapeutic interventions.

  PublisherOA PDFDOI

• Loss of B cell tolerance at the T2/T3a B cell transition is a convergent pathogenic mechanism in common variable immunodeficiency

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-11 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Many patients with common variable immunodeficiency (CVID), including those with CTLA4 deficiency, NFKB1 variants and activated PI3K-delta syndrome (APDS), develop autoimmunity that is refractory to treatment. Despite this shared clinical phenotype, a unifying mechanism for the breakdown of B cell tolerance across monogenic forms of CVID has not been established. Here, we demonstrate that patients with loss-of-function NFKB1 variants, like those with CTLA4 variants and APDS, exhibit dysregulated CD4 + T cell expansion, accumulation of transitional B cells, and a relative lack of follicular B cells. In patients with monogenic CVID and clinical autoimmunity, we observed a relative expansion of transitional and activated naïve (aN: CD21 lo CD11c hi ) B cells in peripheral blood accompanied by a marked increase in the frequency of VH4-34 expressing autoreactive 9G4 + B cells, which expanded between T2 and T3a transitional B cell stages. Single-cell transcriptomic and B cell receptor analysis further revealed a marked expansion of activated T1/2, T3 and extrafollicular activated naïve and double negative (DN: IgD - CD27 - ) B cell subsets in APDS patients. Notably, one B cell subset appeared exclusively in the APDS disease state, characterized by high oxidative phosphorylation in transitional B cells, specifically. In APDS patients, we also observed a clonal expansion of specific extrafollicular class-switched DN B cells, which were clonally derived from activated transitional B cells. DN B cells were also identified in APDS lung tissue, consistent with the contribution of activated, extrafollicularly-derived B cells to tissue inflammation. Together, these findings suggest that in many patients with CVID and autoimmune features, premature activation of autoreactive transitional T2 and T3a B cells induces the survival and expansion, rather than the tolerization and elimination, of self-reactive B cells. This process leads to extrafollicular expansion of autoreactive B cells capable of tissue infiltration. One Sentence Summary Loss of transitional B cell tolerance and extrafollicular expansion of autoreactive B cells drive autoimmunity in monogenic causes of CVID.

  PublisherOA PDFDOI

• Marginal Zone B Cell Development

  Elsevier eBooks · 2025-01-01

  book-chapter1st authorCorresponding
  PublisherDOI

• Smart chains: Designer antibodies shaped by AI

  Science Immunology · 2025-12-05

  articleSenior authorCorresponding

  Antibodies against specific epitopes were designed with assistance from artificial intelligence.

  PublisherDOI

• Two distinct durable human class-switched memory B cell populations are induced by vaccination and infection

  Cell Reports · 2025-04-01 · 11 citations

  articleOpen accessSenior author

  DN1 B cells was also durable, exhibited a unique TP63-linked transcriptional and anti-apoptotic signature, had low levels of somatic hypermutation, but was more clonally expanded than canonical switched-memory B cells. DN1 B cells likely evolved to preserve immunological breadth and may represent the human counterparts of rodent extrafollicular memory B cells that, unlike canonical memory B cells, can enter germinal centers and facilitate B cell and antibody evolution.

  PublisherDOI

• Is one lymphocyte’s brake another lymphocyte’s gas?

  Science Immunology · 2025-02-07 · 1 citations

  articleSenior authorCorresponding

  PD-1 contributes to memory B cell development and robust antibody responses through B cell extrinsic and intrinsic mechanisms.

  PublisherDOI

• A roadmap for defining “extrafollicular” B cell responses

  Immunity · 2025-09-23 · 18 citations

  review
  PublisherDOI

• A LAGging kiss leaves T cells cold

  Science Immunology · 2025-08-01

  articleSenior authorCorresponding

  LAG-3 dampens CD4+ T cell activation by disrupting CDε-Lck condensates and is a therapeutic target in both cancer and autoimmunity.

  PublisherDOI

• An e-Xist-ential two-edged sword for women

  Science Immunology · 2024-03-01

  articleSenior authorCorresponding

  Xist-containing ribonucleoproteins drive autoimmunity in women.

  PublisherDOI

• Evidence Circulating Microclots and Activated Platelets Contribute to Hyperinflammation Within Pediatric Post Acute Sequala of COVID

  2024-04-30 · 4 citations

  article
  PublisherDOI

Recent grants

• NIH Grant R21AI057486

  NIH · $349k · 2006

• NIH Grant R01AI033507

  NIH · $2.3M · 2005

• Administrative Core

  NIH · $14.5M · 2014–2029

• NIH Grant RC1AR058481

  NIH · $997k · 2012

• Human Genetics and Microbiome Core

  NIH · $38.3M · 1997–2027

Frequent coauthors

• Vinay S. Mahajan

  Harvard University

  110 shared

• Cory A. Perugino

  Massachusetts General Hospital

  109 shared

• John H. Stone

  Harvard University

  107 shared

• Hamid Mattoo

  Sanofi (United States)

  94 shared

• Annaiah Cariappa

  Ragon Institute of MGH, MIT and Harvard

  93 shared

• Emanuel Della‐Torre

  Istituti di Ricovero e Cura a Carattere Scientifico

  86 shared

• Takashi Maehara

  Utsunomiya University

  58 shared

• Naoki Kaneko

  University of California, Los Angeles

  56 shared

Labs

• Harvard’s Biochemical Sciences Tutorial ProgramPI

Education

• M.D.

  Harvard Medical School

• Ph.D.

  Harvard Medical School