About

Laurence C Eisenlohr is a Professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania. His research expertise includes the cell biology of MHC class I-restricted antigen processing and presentation, focusing on the rapid presentation of cytosolic and endoplasmic reticulum-targeted proteins and their impact on CD8+ T cell responses. He has demonstrated that processing of antigens targeted to the endoplasmic reticulum is qualitatively and kinetically distinct from cytosolic antigens, and has proposed models to enhance vaccine design targeting the CD8+ T cell compartment. Eisenlohr's work also explores the cell biology of MHC class II-restricted antigen processing, particularly endogenous sources of antigen recognition by CD4+ T cells, challenging traditional paradigms and suggesting alternative pathways involving cytosol delivery and proteasome activity. His research extends to the generation and significance of 'cryptic' epitopes produced by errors during translation, which can be recognized by CD8+ T cells and may influence autoimmunity. Additionally, he applies his immunological insights to cancer immunotherapy, investigating neoantigen formation, tumor-specific phosphopeptides, and the immune response in papillary thyroid cancers caused by the RET/PTC3 fusion protein, as well as exploring targets like the guanalyl cyclase C receptor for metastatic colorectal cancer. His contributions aim to deepen understanding of immune mechanisms and improve vaccine and immunotherapy strategies.

Research topics

• Virology
• Biology
• Genetics
• Immunology
• Medicine

Selected publications

• Conditional T and NK cell antagonism by a giant and highly conserved orthopoxvirus virulence factor

  Research Square · 2026-02-04

  preprintOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Generation and characterization of a novel MHC-II tetramer for tracking and characterization of toxin B-specific CD4 ⁺ T cell responses

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-19

  articleOpen access

  Abstract The gastrointestinal pathogen Clostridioides difficile , is a major burden for health systems due to high rates of recurrence. C. difficile pathogenesis is mediated by two virulence factors, toxin A (TcdA) and Toxin B (TcdB). Antibodies specific for TcdA and TcdB are correlated with protection from symptomatic recurrence, however, the role for CD4 + T cells is poorly understood in part due to the lack of tools to study the toxin-specific CD4 + T cell response. Our group recently demonstrated the antibody and CD4 + T cell response to C. difficile toxins is impaired via the glucosyltransferase activity of the toxins; however, tools do not exist to study the protective capacity and the phenotype of toxin-specific CD4 + T cells. Therefore, we developed an MHC-II tetramer to identify TcdB-specific CD4 + T cells via flow cytometry. Herein, we identified an immunodominant epitope (TcdB 1961-1975 ) in the CROPs region of TcdB and optimized an MHC-II tetramer for use in tracking and phenotyping TcdB-specific CD4 + T cell responses following multiple different immunization strategies in mice. Utilizing the tetramer, TcdB-specific T follicular helper (Tfh) cells were detected following TcdB-CROPs mRNA-LNP vaccination validating the advantage of the tetramer. Furthermore, using a modular mRNA vector expressing the TcdB 1961 peptide covalently bound to the beta chain of MHC-II (MHC-IIβ) we were able to generate a robust population of TcdB-specific CD4 + T cells. These data outline the generation of new tools for the C. difficile field and lay the groundwork for future studies of toxin-specific CD4 + T cell responses.

  PublisherDOI

• Cutting Edge: An mRNA Platform to Create Isolated, Monospecific Th1 Responses

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-27

  preprintOpen accessSenior authorCorresponding

  Abstract Helper T cells (T CD4 ) are lynchpins of adaptive immune responses. Since each T CD4 expresses a single T cell receptor, recognizing an epitope within major histocompatibility complex class II (MHCII), it is often desirable to study a population that responds to the same epitope. We devised a novel method of selective immunization to produce a robust, monospecific T CD4 in mice using a modular mRNA vector. The vector encodes the target epitope attached via flexible linker to MHCII. Immunization with this mRNA selectively elicits T CD4 responses across a range of epitopes and MHCII alleles. These T CD4 show robust, polyfunctional Th1 cytokine release when evaluated in vitro . Additionally, we tested the activity of these T CD4 cells during Salmonella enterica infection, a model of Th1-dependent immune response, and demonstrated their efficacy in vivo in curtailing infection.

  PublisherOA PDFDOI

• An mRNA platform to create isolated, monospecific Th1 responses

  The Journal of Immunology · 2025-12-02 · 1 citations

  articleSenior author

  Helper T cells (CD4 T cells) are lynchpins of adaptive immune responses. Each CD4 T cell expresses a single T-cell receptor, recognizing an epitope presented by major histocompatibility complex class II (MHC-II). Due to the enormous diversity of the T-cell repertoire, it is often desirable to study a population that responds to the same epitope. Here, we devised a novel method of selective immunization to produce a robust, monospecific helper T-cell response in mice using a modular mRNA vector. The vector encodes the target epitope attached via flexible linker to MHC-II. Immunization with this mRNA selectively elicits helper T-cell responses across a range of epitopes and MHC-II alleles. These CD4 T cells show robust, polyfunctional Th1 cytokine release when evaluated ex vivo. We tested the activity of these CD4 T cells in 2 disease models: Salmonella enterica and influenza virus. In both models, these monospecific CD4 T cells influenced the course of infection, demonstrating the utility of this experimental tool, which can produce a monospecific CD4 T-cell response.

  PublisherDOI

• Investigating the impact of the ectromelia virulence factor C15 on early responses to infection in the draining lymph node 9307

  The Journal of Immunology · 2025-11-01

  articleOpen accessSenior author

  Abstract Description Orthopoxviruses, such as variola and Mpox, encode a myriad of immunomodulatory proteins to promote pathogenesis. One notable family is the B22 family of proteins, which are conserved virulence factors that are generally described to inhibit T cell activation in vitro and ex vivo. However, we recently determined that the ectromelia virus (ECTV) B22 protein, C15, also facilitates early viral replication in C57BL/6 mice through the targeting of natural killer (NK) cell-mediated viral control. Current evidence suggests that C15 inhibits cell-cell contacts between NK cells and infected cells, but the immunological consequences and the underlying cellular mechanisms of this inhibition remain unknown. Here, we used flow cytometry as well as transcriptomic analysis to further dissect the immune response within the draining lymph node during WT or ECTVΔC15 infection. Using quantitative PCR, we found that C15 exerts a replicative advantage as early as 32 hours post-infection. Furthermore, in contrast to expected phenotypes, we found significantly more IFNγ+ NK cells 48 hours post-infection with WT ECTV. Bulk RNA sequencing has identified several candidate transcription factors that may underly these phenotypic differences, and future work seeks to use single-cell RNA sequencing to identify key changes within cell subsets. Overall, we conclude that C15 functions between 24 and 32 hours post-infection to modulate innate immune responses and transcriptional responses to infection. Funding Sources Supported by NIH/NIAID R01AI182049-02 and F31AI183694-01 Topic Categories Viral Immunology (VIR)

  PublisherOA PDFDOI

• Multimodal induction of fulminant HLH by IL-18 includes virus-specific NK immunodeficiency

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-08 · 1 citations

  preprintOpen access

  Abstract Macrophage Activation Syndrome (MAS) is a cytokine storm syndrome associated with Still’s Disease, XIAP deficiency, and elevation of both total and free IL-18. Modeling excess IL-18 using Il18tg mice, we found mild NK-cytopenia and cytotoxic T lymphocyte (CTL) activation in resting mice reminiscent of Still’s patients. Infection with Lymphocytic Choriomeningitis Virus (LCMV) triggered MAS via and IFNγ, despite normal viral clearance. Il18tg NK cell transcriptomes showed replicative activity, but few changes in canonical NK function or maturation pathways. LCMV clearance is NK-independent, so we challenged Il18tg mice with mousepox in which NK cells are critical early orchestrators of clearance. Il18tg mice’s NK cells failed to activate or expand, but mousepox further activated their CTL and early viral control was normal. Il18tg mice soon developed “MAS” including hepatosplenic necrosis, but (contrasting with LCMV) they showed poor virus-specific CTL expansion and viral clearance. Though more normal at rest, Il18bp KO mice’s NK cells were similarly inert upon mousepox infection, and the mice succumbed to viremic MAS like Il18tg . Rescue of Il18tg mice, and mousepox-specific CTL responses, by NK cell transfer required in vitro NK pre-activation. Thus, IL-18 can induce both hyperinflammation (CTL hyper activation) and immunodeficiency (NK cell hypo activation) depending on the nature of the infectious trigger.

  PublisherOA PDFDOI

• Oesophageal Epithelial Cell‐Intrinsic <scp>MHCII</scp> Regulates Food Antigen‐Dependent Eosinophilic Esophagitis in an <scp>IFN</scp> γ‐Dependent Manner

  Clinical & Experimental Allergy · 2025-12-22 · 1 citations

  articleOpen access

  BACKGROUND: Eosinophilic oesophagitis (EoE) is a chronic food allergy that causes oesophageal inflammation and dysfunction. Recent work demonstrates IFNγ-dependent gene signatures in inflamed EoE biopsies. IFNγ has been implicated in the promotion of MHCII expression on oesophageal epithelial cells (EECs). However, the regulation of EEC-MHCII expression in vivo, and its contribution to EoE, is unknown. OBJECTIVE: The objective of this study was to determine the regulation and role of EEC-intrinsic MHCII expression in EoE. METHODS: We examined the expression of HLA II-pathway transcripts in human EECs using single cell RNA-seq datasets and primary human tissues and mouse systems to interrogate the contribution of IFNγ to EEC-MHCII expression. Finally, we used a mouse disease model to test the contribution of epithelial MHCII to food antigen-dependent EoE. RESULTS: HLA II transcripts were upregulated in EECs of active EoE patients, compared with controls. Similarly, EEC-MHCII expression was higher in mice with EoE-like inflammation. EEC-MHCII expression was governed by IFNγ-responsive transcriptional regulation. EEC-specific MHCII deficiency resulted in exacerbated eosinophilic inflammation in a model of food antigen-dependent EoE. CONCLUSION: We find a novel immunoregulatory role for IFNγ-dependent EEC-MHCII in the context of oesophageal food allergy. CLINICAL RELEVANCE: Our results expand our understanding of oesophageal immune physiology and identify EEC-MHCII as mediating an anti-inflammatory axis that could be leveraged therapeutically.

  PublisherOA PDFDOI

• Scar wars: the viral menace

  American Journal of Physiology-Lung Cellular and Molecular Physiology · 2025-09-23 · 1 citations

  reviewOpen access

  Pulmonary fibrosis (PF) is a severe consequence of respiratory infections, characterized by excessive extracellular matrix deposition and irreversible lung architectural damage. Once considered a rare condition, PF is now increasingly recognized in the wake of viral infections, particularly among survivors of viral-induced acute respiratory distress syndrome (ARDS). The COVID-19 pandemic has highlighted in bold relief the observation that many survivors of severe viral pneumonia do not recover fully but develop chronic fibrotic changes that impair lung function. This review examines the clinical evidence and underlying mechanisms linking viral infections-COVID-19, influenza, and other respiratory viruses-to the onset of pulmonary fibrosis. By probing the mechanisms of cellular injury, immune dysregulation, and aberrant repair mechanisms, we aim to illuminate the pathways that transform an acute viral insult into a chronic, fibrotic disease.

  PublisherDOI

• A Unique in vivo Approach to Producing Epitope-specific MHCII TCR-like Antibodies 9257

  The Journal of Immunology · 2025-11-01

  articleOpen accessSenior author

  Abstract Description The ability to observe, detect, and track the presentation of specific epitopes via major histocompatibility complex II (MHCII) can be a valuable tool in the context of many immunological questions. The current available methods most often used, such as, mass spectrometry, T-cell recognition and ELISPOT assays are limited in their utility and functionality, while soluble T cell receptors (TCR) have proven to be difficult to engineer and often have low affinity for their target. TCR-like antibodies capable of recognizing epitope-specific MHCII with high affinity and specificity are a preferable tool in many cases. However, current methods of TCR-like antibody production are time intensive and often require the building of comprehensive antibody libraries with multiple rounds of selection to determine antibodies of high affinity for their target. Therefore, we sought to develop a reliable and efficient pipeline capable of producing epitope-specific TCR-like antibodies of high affinity without the need for in vitro affinity optimization. Here we utilize lipid nanoparticle delivery of single-chain peptide-MHCII mRNA constructs to mice and rely on the in vivo antibody maturation process and rigorous selection of high affinity clones to develop monoclonal TCR-like antibodies. Through our pipeline we can successfully produce TCR-like antibodies of high affinity and specificity, and we continue to optimize it to do so consistently and reliably. Funding Sources Supported by NIAID 1R01AI180250-01A1 Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)

  PublisherOA PDFDOI

• Scar Wars: The Viral Menace

  2025-03-10

  preprintOpen accessSenior author

  Pulmonary fibrosis (PF) is a formidable consequence of severe respiratory infections, marked by excessive extracellular matrix deposition and irreversible lung architectural damage. Once considered a rare and obscure sequela, PF is now increasingly recognized in the wake of viral infections, particularly among survivors of viral-induced acute respiratory distress syndrome (ARDS). The COVID-19 pandemic has cast a spotlight on this phenomenon, revealing a stark reality: many patients who endure severe viral pneumonia do not fully recover, instead developing persistent fibrotic changes that compromise lung function. This review unpacks the clinical evidence and underlying mechanisms linking viral infections—COVID-19, influenza, and other respiratory viruses—to the onset of pulmonary fibrosis. By delving into cellular injury, immune dysregulation, and aberrant repair mechanisms, we aim to illuminate the pathways that transform an acute viral insult into a chronic, fibrotic disease.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R21AI063065

  NIH · $421k · 2009

• NIH Grant R01AI039501

  NIH · $3.7M · 2012

• NIH Grant R01AI100561

  NIH · $1.2M · 2017

• NIH Grant T32CA009683

  NIH · $2.4M · 2009

• NIH Grant R56AI101134

  NIH · $519k · 2015

Frequent coauthors

• Jack R. Bennink

  National Institute of Allergy and Infectious Diseases

  42 shared

• Gabriela L. Cosma

  Thomas Jefferson University

  34 shared

• Jonathan W. Yewdell

  National Institute of Allergy and Infectious Diseases

  31 shared

• Michael A. Miller

  Atrium Health Wake Forest Baptist

  30 shared

• Nicholas A. Siciliano

  Leavitt Partners (United States)

  29 shared

• Adam E. Snook

  25 shared

• Nancy Luckashenak

  Johnson & Johnson (United States)

  25 shared

• Michael J. Hogan

  Children's Hospital of Philadelphia

  24 shared

Labs

• Eisenlohr LabPI

Education

• Ph.D., Immunology

  University of Pennsylvania

  1988

• V.M.D.

  University of Pennsylvania School of Veterinary Medicine

  1983

• B.A., Biology

  Haverford College

  1979