About

Michael R. Betts, PhD, is a Professor of Microbiology at the University of Pennsylvania's Perelman School of Medicine. His research focuses on human T lymphocyte function, particularly in understanding how these cells control or eliminate viral pathogens and provide protection from infection. His primary interest is in the human CD8+ T cell response to HIV and its role in controlling viral replication. Betts also studies immune responses against other human pathogens such as Epstein-Barr virus, cytomegalovirus, influenza, and vaccinia virus, utilizing advanced techniques like polychromatic flow cytometry to analyze T cell functions in detail. His laboratory aims to elucidate the mechanisms that govern the fate and functional characteristics of HIV-specific T and B cells during infection and disease progression. Betts's work includes characterizing the human T cell response to various vaccine regimens designed to generate cell-mediated immunity, with the goal of understanding the principles underlying vaccine-mediated immune protection. His contributions have advanced the understanding of T cell responses in viral infections, particularly HIV, and his research employs cutting-edge methods to explore immune responses, contributing significantly to the field of viral immunology.

Research topics

• Biology
• Immunology
• Medicine
• Virology
• Pathology
• Computer Science
• Genetics
• Computational biology
• Molecular biology
• Internal medicine
• Intensive care medicine

Selected publications

• Abstract 276: Anti-tumor activity in humanized xenograft models and B-cell aplasia in non-human primates with a novel CD3-directed in vivo gene-modifying CAR (GCAR) lentivector encoding chimeric antigen receptors and a cellular fitness-enhancing co-stimulatory protein.

  Cancer Research · 2026-04-03

  article1st authorCorresponding

  Abstract Introduction: An in vivo gene-modifying CAR (GCAR) platform has been developed to mitigate known clinical and logistical challenges with traditional ex-vivo manufactured CAR-T products. The GCAR platform incorporates an NHP/human reactive CD3-targeted lentivector (LVV) with complement resistant fusogen that encodes CD3zeta based CARs and a compact synthetic costimulatory protein (FD) optimized for proliferation, persistence, and cytotoxicity. The ability of GCAR LVVs to elicit potent, specific and persistent cytotoxicity towards target cells was evaluated in vitro and in humanized and non-human primate models. In M. nemestrina, GCAR CD20 CAR was evaluated for B-cell depletion compared to LVVs encoding conventional 41BB CARs without FD. Methods: Anti-CD19 or anti-CD20 LVV’s manufactured from 6L and 25L scales were characterized for CD3 reactivity in M. nemestrina and human PBMC in vitro and in vivo. Serum complement sensitivity and activation assays were used to characterize GCAR LVVs (encoding anti-CD20 CAR and FD) against human and NHP sera and CD3 positive lymphocytes. Escalating doses (IV or IN) of purified LVV’s were evaluated in the NHPs. B-cells were quantified by flow cytometry and safety by clinical chemistry, hematology, and physical assessments. Results: Exposure of human or nemestrina PBMC to GCAR LVVs resulted in dose and target-dependent cell lysis with rapid tumor clearance in Raji-Luc disseminated PBMC-humanized DKO NSG models. In CD34-humanized models, GCAR LVV generated CAR-T cells with durable B-cell depletion over >8 weeks of observation. Administration of GCAR CD20 LVV (IV or IN) was well tolerated in NHPs at all doses w/o severe CRS or neurologic toxicity. B-cell depletion kinetics post IV dosing of CD20 CARs with FD were dose dependent: minimally active doses demonstrated delayed onset of B cell depletion (from day 21 post dose) vs. B cell aplasia by day 7 at the most active doses. In contrast, a comparable GCAR LVV encoding 41BB CD20 CAR (w/o FD) by IV and IN injection elicited B cell depletion at 7 days post dose with reduced duration. Conclusion: GCAR LVVs generated genetically modified lymphocytes resulting in durable CAR-dependent cell removal across mechanistic, murine, humanized, and NHP immune systems. The incorporation of FD may further improve cellular expansion and persistence, yielding ex vivo-like CAR-T activity profiles without lymphodepletion or cytokine support. The absence of acute and subacute safety signals, low off-target transduction, serum complement resistance, and deep B-cell depletion support the GCAR platform as a potential next-generation opportunity for clinical investigation as a novel gene modifying CAR approach. Citation Format: Michael Betts, Matilda Mostrom, Ewa A. Jaruga-Killeen, Frederic Vigant, Anirban Kunda, Michelle Andraza, Cody Gowan, Iryna Oliinyk, Gregory Wade, Gregory Schreiber, Carter Bir, Jason P. Dufour, Robert V. Blair, Nicholas J. Maness, H. Michael Shepard, Gregory Ian Frost. Anti-tumor activity in humanized xenograft models and B-cell aplasia in non-human primates with a novel CD3-directed in vivo gene-modifying CAR (GCAR) lentivector encoding chimeric antigen receptors and a cellular fitness-enhancing co-stimulatory protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 276.

  PublisherDOI

• Single cell characterization of the gastrointestinal HIV reservoir reveals heterogeneous cellular phenotypes

  UNC Libraries · 2026-02-20

  articleOpen access

  Human gastrointestinal (GI) tissues are a major site of HIV-1 viral persistence, but the nature of the GI reservoir remains poorly described. To characterize the GI HIV reservoir, we profiled cells from GI tissue and matched peripheral blood mononuclear cells from ten people with HIV on antiretroviral therapy using single cell RNA sequencing. We identified distinct compartment-specific patterns of gene expression, highlighting key differences between blood and colon CD4 T cell populations. vRNA+ cells from both blood and GI tissue were heterogeneous and found in multiple subtypes of CD4 T cells, although vRNA+ cells were particularly enriched in cells with Th17 or Treg17 phenotypes. Transcriptomic comparison of HIV vRNA+ and vRNA- T cells revealed 116 differentially expressed genes that were associated with HIV infection including ZBED2, MAF and IL17F. These data provide novel information regarding the GI-resident HIV reservoir and suggest that compartment-specific patterns of gene expression are associated with HIV infection.

  PublisherDOI

• Spatial transcriptomics from pancreas and local draining lymph node tissue reveals a lymphotoxin-β signature in human type 1 diabetes

  Cell Reports · 2026-03-23

  articleOpen access

  This study explores the inflammatory response observed in the pancreas and pancreatic lymph nodes (pLNs) during the natural history of type 1 diabetes (T1D). Using multicell-resolution spatial transcriptomics (ST), we profile individuals without diabetes (ND), at-risk autoantibody-positive (AAb+) individuals, and T1D donors. In the T1D pancreas, we observed global upregulation of inflammation-associated transcripts, including REG family genes, C3, SOD2, and OLFM4. In the T1D pLN, LTB was significantly upregulated within the lymphoid follicles. Using an orthogonal subcellular-resolution ST platform on an independent donor set, we identified follicular B cells as the primary source of LTB in the pLN and observed increased LTB expression in lymphocytes in insulitic lesions proximal to CCL19/CCL21-expressing endothelium. Collectively, these findings highlight lymphotoxin-β and downstream chemokine signatures in the pancreatic lymphatics as well as within the insulitic lesion, which can inform future therapeutic interventions.

  PublisherDOI

• Clinical trial results provide the rationale to protect dual HIV-specific T cells with a signaling-defective HIV fusion inhibitor

  Molecular Therapy · 2026-01-10

  articleOpen access
  PublisherOA PDFDOI

• Differential Contributions of IgM and IgG Autoantibodies to Serologic IA2 Reactivity in Type 1 Diabetes

  Biomolecules · 2026-03-26

  articleOpen access

  Autoantibodies targeting islet antigen 2 (IA2) are critical diagnostic and prognostic markers for type 1 diabetes (T1D). Standard clinical assays do not differentiate between IgG and IgM isotypes, yet these antibodies have distinct roles in the T1D autoimmunity. We therefore adapted electrochemiluminescence (ECL) assays to separately detect IgG and IgM antibodies against the IA2 intracellular domain (AA601-979). Assay specificity was confirmed by indirect immunofluorescence, which showed autoantibody binding to IA2-overexpressing cells. Plasma samples were analyzed from two independent cohorts: organ donors of the Human Pancreas Analysis Program (HPAP, n = 69) and children from a Janssen–Breakthrough T1D-funded study (n = 65). Diabetics had significantly higher levels of IA2 IgG (p < 0.001) but not IgM (p > 0.05) compared with controls. Notably, IgM and IgG IA2 antibody levels were not correlated. However, IgM modulates IgG detection: IgM depletion increased detected IgG levels to IA2 in some donors, and sera from donors with high IA2-specific IgM levels reduced monoclonal IgG anti-IA2 antibody binding to IA2. Purified IgM from healthy individuals also suppressed monoclonal IgG binding. These findings support distinct, non-redundant roles for IA2-specific IgG and IgM in T1D serology. Isotype-specific autoantibody analysis may improve risk stratification and monitoring of T1D individuals receiving immunomodulatory therapies.

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• Abstract 482: Development of a CD3-targeted lentiviral vector compatible with M. <i>nemestrina</i> to evaluate in vivo CAR-T gene therapy

  Cancer Research · 2025-04-21

  article

  Abstract While LV gene transfer into human lymphocytes is well-characterized, most non-human primate species carry TRIM5α restriction factors that limit the sensitivity for in vivo biodistribution and RCL safety assessments. While LV targeting T cells through the TCR complex can both provide activation signals in the process of endocytosis, envelopes with broad tropism may also cause unintended transduction of other cell types. Additionally, immune complement mediated inactivation of envelope proteins may influence biodistribution. In this study, CD3-targeted LV’s were redesigned for reactivity with both human and M. nemestrina. A modified pH-dependent fusogen was also incorporated into the LV envelope for endosomal escape following CD3-mediated endocytosis. The impact of envelope design on serum resistance, cell tropism, T cell activation, and CAR-T expansion using in vitro cultures of isolated NHP PBMC compared to human PBMC. 3rd generation SIN vectors with codon modified GAGPOL sequences were utilized to mitigate risks of vector remobilization. Methods: PBMC from M. nemestrina or human donors were used fresh or cryopreserved. SIN LV variants encoding a primatized α -CD20 CAR transgene +/- a synthetic lymphoproliferative element with EGFR cell removal epitope were manufactured in a 5-plasmid system including transmembrane or GPI anchored NHP/human cross-reactive CD3 targeting moieties and pH dependent fusogens. LV titers, specific activities, CD3 signaling, and LV endocytosis were characterized for each vector. Immunophenotype, CAR-T expansion and functionality of LV-treated cells were analyzed by flow cytometry and cytokine analysis. Results: Several α-CD3 scFv targeting elements presented on the LV surface showed weak CD3 stimulating activity but could be stabilized through incorporation of additional protein domains. One α-CD3 scFv (NCD3) was identified with strong CD3 stimulation of both human and M. nemestrina T cells in transmembrane or GPI configuration. LV constructs with human-only reactive CD3 targeting moieties showed no transduction or stimulation of M. nemestrina PBMC while effectively modifying human PBMC as expected. NCD3 targeting LV constructs were shown to effectively transduce both M. nemestrina and human T cells, generating CAR-T cells capable of expansion and response to antigen re-challenge. No transduction was observed using a pH dependent fusogen on CD3 negative cells compared to VSV-G envelope controls. Finally, LV constructs expressing the NCD3 targeting moiety and fusogen retained greater than 50% activity across multiple serum donors, demonstrating resistance to complement mediated inactivation. Conclusion: A CD3 targeting LV construct capable of activating and transducing both human and NHP PBMC in a CD3 specific fashion was successfully engineered as a product suitable for testing biodistribution, potency and RCL in an NHP model. Citation Format: Anirban Kundu, Frederic Vigant, Cody Gowan, Michael Betts, Ewa Jaruga-Killeen, Gregory Schreiber, Michelle Andraza, Gregory I. Frost. Development of a CD3-targeted lentiviral vector compatible with M. nemestrina to evaluate in vivo CAR-T gene therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 482.

  PublisherDOI

• Transient tissue residency and lymphatic egress define human CD56bright NK cell homeostasis

  Nature Immunology · 2025-10-14 · 5 citations

  articleOpen access

  Abstract Human tissue-resident (TR) CD56 bright natural killer (NK) cells can be identified by expression of integrins and chemokine receptors inferred from murine studies, but many aspects of their homeostasis are unclear. Here we used an integrated approach of dynamic human, humanized mouse and non-human primate models and sampling of efferent lymph fluid to determine recirculation and TR patterns of human NK cells. By intravascular labeling, we showed that CD56 bright NK cells access tissue niches at steady state. Furthermore, in human liver transplantation, donor-derived CD56 bright NK cells represent the dominant TR NK cell population early after transplantation, but are replaced over time by infiltrating recipient NK cells that establish TR traits, a process partly regulated by Runx3. Transient TR CD56 bright NK cells recirculated via lymphatics, displaying a consistent phenotype detectable in draining lymph nodes and efferent lymph fluid, and waned from peripheral blood on lymph node egress blockade. Finally, CD56 dim NK cells, constrained to vasculature at steady state, entered lymph nodes upon inflammation. This study provides a mechanistic framework for the transient tissue residency and recirculation pattern of human NK cell populations.

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• Decoding the immune cells in the fetal brain at murine mid-gestation 4687

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Adverse events during gestation can influence long-term offspring immunity by disrupting key fetal developmental milestones. Inflammation can alter the emergence of several fetal immune subsets, however, these studies primarily focus on maternal factors that govern development leaving fetal contributions unknown. Fetal immunity is best characterized in context of the liver, the site of fetal hematopoiesis at mid-gestation. We used a high-dimensional sequencing technology, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), that allowed us to simultaneously study surface protein markers and gene expression at a single-cell resolution. Interestingly, we identified two multipotent progenitor cell subsets present in the fetal brain at mid-gestation. The presence of progenitor immune cells in the fetal brain highlights its susceptibility to inflammatory events that occur during development. Therefore, we sought to further characterize the phenotype of immune cells in fetal brain with respect to the fetal liver isolated from murine implantation sites at mid-gestation. We identified eleven clusters of immune cells shared by both the fetal brain and liver, ten of which are of innate immune cells at various stages of development, including both multipotent progenitor populations. Our findings provide foundation to understand fetal immune development and will lead to future work studying the consequences of gestational inflammation on the fetal immune system. Funding Sources Howard Hughes Medical Institute through the Gilliam Fellows Program Topic Categories Neuroimmunology (NEUR)

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• Dysregulated lymphocyte localization in idiopathic multicentric Castleman disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-15 · 1 citations

  articleOpen access

  Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening hematologic disease involving episodic flares of uncontrollable systemic inflammation by unknown causes. Hallmark features of iMCD include multiple enlarged lymph nodes with characteristic histopathological phenotypes and a potentially fatal, cytokine release syndrome. The key pathophysiologic drivers of disease are poorly understood and few effective treatment options exist. Here, we discovered an association between elevated chemokines, namely CXCL13, and lymph node size in iMCD, providing one possible explanation for the lymphadenopathy observed clinically. Instead of a concurrent increase in circulating CXCL13 and CXCR5-expressing cells that has been described in other contexts, during active disease, chemokine-responsive lymphocytes downregulated CXCR5 levels in iMCD. Despite heightened chemokine production by lymph node stromal cells, T and B cells failed to appropriately respond to their cues locally within the tissue and were particularly scarce within CXCL13-expressing germinal centers (GC). Inflammatory signals in iMCD lymph nodes appeared to restrict the production and movement of T follicular helper cells, which play an important role in facilitating appropriate GC responses. Together, these data provide a link between dysregulated chemokine production and germinal center lymphocyte trafficking, highlighting a potential mechanism and therapeutic target in iMCD lymphadenopathy. One Sentence Summary: Lymphocyte chemotaxis to discrete areas of lymphoid tissue is disrupted in idiopathic multicentric Castleman disease.

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• Investigating the immunological effect of MYCN depletion in MYCN-amplified neuroblastoma 9167

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Neuroblastoma, a pediatric cancer with poor responsiveness to immune checkpoint inhibitors, is characterized by low HLA expression, low tumor mutation burden, and low NK- and T-cell infiltration, especially in MYCN-amplified tumors. MYCN is linked to these immunologically cold traits, but its role in shaping the tumor-immune microenvironment (TIME) and immune responses remains poorly understood. We evaluated the efficacy of MYCi975, a MYCN-MAX dimerization disrupter, on MYCN-amplified neuroblastoma cell viability and MYCN target gene expression, and investigated the impact of MYCN depletion on regulating genes involved in innate and adaptive immunity. MYCi975 induced MYCN degradation, reducing viability and transcriptional activity. Flow cytometry revealed upregulation of death receptor 5 (DR5) and HLA-G, but no changes in other NK- or T-cell ligands or classical HLA proteins. This upregulation appeared specific to MYCN depletion, as it was absent in cells treated with doxorubicin or etoposide. MYCi975 also enhanced NK-cell mediated killing of MYCN-amplified cells in the presence of dinutuximab, an FDA-approved anti-GD2 monoclonal antibody for high-risk neuroblastoma, and reduced secretion of the immunosuppressive cytokine IGFBP-2. These findings reveal a mechanism by which MYCN influences anti-tumor immunity and suggest a broader role in TIME modulation, providing a foundation for exploring the therapeutic potential of HLA-G and DR5 co-upregulation with MYCN targeting. Funding Sources This work was funded by NIH grant U54 CA232568, NIH grant R5 CA220500 and the Alex’s Lemonade Stand Foundation. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01AI076066

  NIH · $4.6M · 2019

• NIH Grant R56AI106481

  NIH · $760k · 2015

• Penn integrated Human Pancreas procurement and Analysis Program

  NIH · $17.8M · 2016–2021

• Viral control mechanisms of HIV-specific T cells in HIV-infected lymph node

  NIH · $3.3M · 2015–2021

• NIH Grant P30DK047757

  NIH · $14.2M · 2019

Frequent coauthors

• E. John Wherry

  University of Pennsylvania

  91 shared

• Richard A. Koup

  90 shared

• Daniel C. Douek

  National Institute of Allergy and Infectious Diseases

  79 shared

• Marcus Buggert

  Karolinska Institutet

  72 shared

• Yvette Edghill‐Smith

  National Cancer Institute

  65 shared

• Genoveffa Franchini

  National Cancer Institute

  64 shared

• János Nacsa

  Institute for Computer Science and Control

  64 shared

• Brigitte Beer

  Southern Research Institute

  64 shared

Labs

• Betts LabPI

Education

• PhD, Microbiology and Immunology

  University of North Carolina

  1998