About

Michael Paul Cancro, Ph.D., is Vice Chair for Faculty Development and Academic Affairs in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania. His research focuses on B lymphocyte development, selection, and homeostasis, as well as the immunobiology of aging. His laboratory has made significant contributions to understanding B cell development, including defining the transitional B cell subset and elucidating how cytokine BLyS (BAFF) and its receptors control peripheral B cell selection and numbers. More recently, his work has centered on the discovery of a novel B cell subset called Age Associated B cells (ABCs), characterized by the expression of the transcriptional regulator Tbet. This subset enlarges continuously with age and includes spleen-resident memory B cells that are crucial for anti-microbial immunity but are also expanded in autoimmune diseases. His ongoing research aims to understand the origins of ABCs and their roles in protective immunity and autoimmune conditions.

Research topics

• Biology
• Immunology
• Genetics
• Internal medicine
• Virology
• Molecular biology
• Biochemistry
• Medicine

Selected publications

• T-bet+CD11c+ age-associated B cells resist BLyS- and CD20-targeted ablation in murine lupus models

  Journal of Autoimmunity · 2025-04-01 · 3 citations

  articleOpen accessSenior author

  B cell ablation strategies show promise for treating humoral autoimmune diseases, but their impact on pathogenic tissue-localized T-bet + CD11c + age-associated B cells (ABCs) is poorly defined. We assessed whether mAb-mediated B cell depletion impacts ABCs and other splenic B cell subsets in two mouse models of lupus. Following disease onset, we injected NZBxNZWF1 mice (NZBWF1; n = 72) or bm12 chronic graft versus host disease mice (cGVHD; n = 59) with 0.2 mg or 1 mg of anti-BLyS (10F4), anti-CD20 (18B12), combined treatment, or saline. Spleens were harvested after two weeks and B cell subset representation was analyzed via flow cytometry. In the NZBWF1 model, lymphopenia and resistance to 10F4 and 18B12 that arose concomitant with disease onset complicated interpretation, as ablative activity was partial and variable in the follicular (FO) and marginal zone (MZ) pools. Conversely, the T-bet + CD11c + ABC pool was unchanged or enlarged versus controls and was entirely refractory to antibody treatments. In the cGVHD model, both 10F4 and 18B12 treatments ablated nearly all FO B cells. MZ B cells were profoundly ablated by 10F4 but spared by 18B12 treatment, whereas 10F4 treatment spared a small, undefined subset of splenic B cells that was ablated by 18B12. In contrast, T-bet + CD11c + ABCs were minimally impacted by either reagent alone or combined, regardless of dose. The spleen-resident T-bet + CD11c + ABC pool resists anti-BLyS and anti-CD20 ablative treatment. These findings have implications for antibody-mediated ablative strategies in patients with autoimmune diseases. • Anti-CD20 or anti-BLyS spare some splenic B cell subsets in mouse lupus models. • Combined anti-CD20/anti-BLyS yields complimentary subset ablation. • Neither anti-CD20 nor anti-BLyS deplete splenic age-associated B cells.

  PublisherDOI

• B cells and aging: a historical perspective

  The Journal of Immunology · 2025-03-19 · 1 citations

  article1st authorCorresponding
  PublisherDOI

• Normal Treg homeostasis and suppressive function require both FOXP1 and FOXP4

  JCI Insight · 2025-08-12 · 4 citations

  articleOpen access

  FOXP3+ Treg cells are critical for immune tolerance. Genetic deletion of the Forkhead domain-containing proteins of the FOXP-subfamily member FOXP1 from Tregs results in impaired function associated with reduced CD25 expression and IL-2 signaling, but to date the only other FOXP family member expressed in Tregs, FOXP4, has been minimally studied. To investigate the potential functional interactions among FOXP family members in Tregs, we specifically deleted Foxp1, Foxp4, or both in FOXP3+ committed Tregs in mice. Our findings show that mice with combined, but not individual, deficiency in FOXP1 and FOXP4 exhibit lymphoproliferation, inflammation, autoimmunity, and early lethality. The combined absence of FOXP1 and FOXP4 in Tregs results in an activated/effector-like phenotype with compromised suppressive function in peripheral lymphoid organs, an enhanced germinal center response, and proinflammatory cytokine production. We further show that FOXP1 and FOXP4 bind to Il2ra promoter regions to regulate CD25 expression in Tregs. Through pairwise comparison among mouse strains with Treg-specific deletion of Foxp1, Foxp4, or both, our findings indicate a nonredundant but insufficient role of FOXP4 in Treg function.

  PublisherOA PDFDOI

• T-bet–expressing B cells promote atherosclerosis in apolipoprotein E–deficient mice

  The Journal of Immunology · 2025-02-26 · 4 citations

  articleOpen accessSenior author

  The humoral immune system influences the development of atherosclerosis, but the contributions of specific memory B cell subsets and IgG isotypes are poorly understood. We assessed the relationship between atherosclerosis and age-associated B cells (ABCs), a T-bet-expressing memory B cell subset that is enriched for IgG2c production and implicated in humoral autoimmunity. We found increased numbers of splenic CD11c+ ABCs in 6-mo-old, chow-fed Apoe-/- mice versus C57BL/6 control mice, which were exacerbated by high-fat diet. Deletion of T-bet in the B lineage in high-fat diet-fed Apoe-/- mice reduced aortic lesion area, and this correlated with decreased splenic CD11c+ B cells and reduced serum oxidized low-density lipoprotein-specific IgG2c. Our findings suggest that T-bet-expressing B cells are atherogenic agents in the Apoe-/- model and indicate that interventions to inhibit a T-bet-driven humoral response may improve atherosclerotic disease.

  PublisherOA PDFDOI

• 132 Expansion of Tbet+ T and B cells in the lung of hypomorphic Rag1 mice

  Clinical Immunology · 2024-04-23

  article
  PublisherDOI

• <i>Xist</i> Deletion in B Cells Results in Systemic Lupus Erythematosus Phenotypes

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-18 · 14 citations

  preprintOpen access

  SUMMARY Systemic lupus erythematosus (SLE) is an autoimmune disease preferentially observed in females. X-linked gene expression in XX females is normalized to that of XY males by X-Chromosome Inactivation (XCI). However, B cells from female SLE patients and mouse models of SLE exhibit mislocalization of Xist RNA, a critical regulator of XCI, and aberrant expression of X-linked genes, suggesting that impairment of XCI may contribute to disease. Here, we find that a subset of female mice harboring a conditional deletion of Xis t in B cells (“Xist cKO”) spontaneously develop SLE phenotypes, including expanded activated B cell subsets, disease-specific autoantibodies, and glomerulonephritis. Moreover, pristane-induced SLE-like disease is more severe in Xist cKO mice. Activated B cells from Xist cKO mice with SLE phenotypes have increased expression of proinflammatory X-linked genes implicated in SLE. Together, this work indicates that impaired XCI maintenance in B cells directly contributes to the female-bias of SLE.

  PublisherOA PDFDOI

• Directing risky traffic in B cells with TNIP1

  Nature Immunology · 2024-07-26

  article1st authorCorresponding
  PublisherDOI

• <scp>ABCs</scp> begin with <scp>ZEB2</scp>

  Immunology and Cell Biology · 2024-03-25 · 4 citations

  letterOpen accessSenior authorCorresponding

  Age-associated B cells (ABCs) are a stable subset of memory B lymphocytes that develop during microbial infections and in autoimmune diseases. Despite growing appreciation of their phenotypic and functional characteristics, the transcriptional networks involved in ABC fate commitment and maintenance have remained elusive. In their recent publication, Dai et al. tackle this problem, leveraging both mouse models and human diseases to reveal zinc finger E-box-binding homeobox 2 (ZEB2) as a key transcriptional regulator of ABC lineage specification. In aggregate, their results show that ZEB2, a member of the zinc finger E homeobox binding family, promotes ABC differentiation by repressing alternative differentiative fates and targeting genes important for ABC character and function. Moreover, their results strengthen the case for causal links between ABC fate and function in autoimmune pathologies.

  PublisherOA PDFDOI

• 171 Assessment and Characterization of Tbet+ B Cells in Various Inborn Errors of Immunity (IEIs)

  Clinical Immunology · 2024-04-23

  article
  PublisherDOI

• Partial RAG deficiency induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells

  Clinical Immunology · 2023-05-01

  article
  PublisherDOI

Recent grants

• NIH Grant R01AI073939

  NIH · $2.1M · 2012

• NIH Grant R01AI042990

  NIH · $1.0M · 2002

• NIH Grant R01AI054488

  NIH · $1.9M · 2009

• NIH Grant R01AG016841

  NIH · $1.1M · 2005

• Immune System Development and Regulation

  NIH · $4.2M · 2003–2026

Frequent coauthors

• Jean L. Scholz

  University of Pennsylvania

  39 shared

• Mark J. Shlomchik

  University of Pittsburgh

  28 shared

• Lynn G. Hannum

  Colby College

  25 shared

• Matthew H. Levine

  University of Pennsylvania

  25 shared

• Charles A. Janeway

  St. John’s Health Sciences Centre

  25 shared

• Derek B. Sant’Angelo

  Johnson University

  25 shared

• Ann M. Haberman

  Yale University

  25 shared

• Norman R. Klinman

  24 shared

Education

• Master of Letters, Honorary

  University of Pennsylvania

  1984

• Post doctoral, Pathology/Immunology

  University of Pennsylvania

  1978

• Ph.D. (Genetics, Cancer Biology), Zoology

  University of Maryland

  1976

• Bachelor of Science, Zoology

  University of Maryland

  1972