Faculty

Laurence C Eisenlohr VMD/PhD

faculty photo
Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
The Children's Hospital of Philadelphia
1107B Abramson Research Center
3615 Civic Center Blvd.
Philadelphia, PA 19104-4399
Office: 215 590-0952
Lab: 215 590-5192
Education:
BS (Biology)
Haverford College , 1979.
VMD (Veterinary Medicine)
University of Pennsylvania, 1983.
PhD (Immunology)
University of Pennsylvania, 1988.
Permanent link
 
> Perelman School of Medicine   > Faculty   > Details

Description of Research Expertise

Four Areas of Interest:

1. The cell biology of MHC class I-restricted antigen processing and presentation: My laboratory continues to explore the forces that drive the extremely rapid MHC class I-restricted presentation of both cytosolic and endoplasmic reticulum-targeted proteins, and how differential processing could impact both the induction and effector phases of CD8+ T cell responses. We have demonstrated that processing of antigen targeted to the endoplasmic reticulum is both qualitatively and kinetically distinct from antigen targeted to the cytosol. In addition, we have proposed a model in which the almost instantaneous processing of cytosolic antigens is not due to defectiveness on the part of the antigen but, rather, unchaperoned nascent peptide. Our efforts could enhance the rational design of vaccines that are intended to target the CD8+ T cell compartment.

2. The cell biology of MHC class II-restricted antigen processing and presentation: A generally accepted paradigm in fundamental immunology is that CD4+ T cells recognize peptides derived from exogenous (internalized) sources of antigen while CD8+ recognize peptides derived from endogenous sources of antigen (generally, proteins synthesized within the antigen-presenting cell). I have had a longstanding interest in MHC class II-bound peptides derived from endogenous sources of antigen. As a graduate student I reported on an epitope within the influenza neuraminidase (NA) molecule that can only be presented from endogenously produced NA. No amount of exogenous, inactivated virus, displaying abundant amounts of NA at the virion surface, could be converted to class II-bound peptide by antigen-presenting B cells. Subsequently, my laboratory demonstrated that this NA epitope and another residing within the hemagglutinin molecule are produced by a processing pathway that is much more class I-like in character, involving delivery of antigen to the cytosol, and being dependent upon activity of both the proteasome and TAP (transporter associated with antigen processing). Recently, we have assessed the prevalence of this alternative, endogenous MHC class II-restricted antigen processing. We have found that a variety of endogenous processing pathways are the major drivers of the primary CD4+ T cell response to influenza and also rabies. These findings should fundamentally alter a cornerstone principle of basic immunology and, consequently, rational vaccine design. It should also expand the potential scenarios for the development of autoimmune disease and the potential targets for cancer immunotherapy.

3. "Cryptic" MHC Class I-Restricted Epitopes: In MHC class I antigen processing and presentation, my laboratory has also explored the generation and significance of “cryptic” epitopes that are produced by errors during translation. Thus, protein synthesis will occasionally initiate at an internal start codon, the ribosome having failed to decode the first AUG. Likewise, during translation the ribosome can, at low frequency slip into an alternative reading frame. In both cases we have demonstrated that these aberrations may have no biological significance but can be readily recognized by CD8+ T cells. Most recently, we have made a similar observation with respect to the low level of stop codon recoding that is induced in eukaryotic cells by aminoglycoside antibiotics. In this case, we identified by tandem mass spectrometry numerous class I-bound recoded peptides in gentamycin-treated cells but not their control counterparts. Thus, the immunological definition of “self” and “foreign” changes in the presence of these antibiotics, providing a potential mechanism for induction of autoimmunity.

4. Cancer immunotherapy and autoimmunity: For several years we have applied our experience in viral immunity to the very challenging area of cancer immunotherapy. One area of focus is papillary thyroid cancers caused by the RET/PTC3 (RP3) fusion protein. Despite not having a viral etiology, RP3 causes neoantigen formation via aberrant phosphorylation, resulting in the presentation of tumor-specific phosphopeptides (“signal 1” for T cell activation) and activates NF-kappaB, resulting in release of proinflammatory cytokines from tumor cells (the co-stimulatory “signal 2”). First in collaboration with the Rothstein lab and then on our own we have been pursuing the hypothesis that RP3-induced papillary thyroid cancer is relatively benign because it induces a robust, effective T cell response that keeps the cancer in check. We have published evidence to this effect and demonstrated that the transforming and inflammation-inducing signals emanating from RP3 can be functionally dissociated. The work provides an important counterbalance to the notion that inflammation abets cancer progression. In addition, we have collaborated with the Waldman lab at Thomas Jefferson University in exploring viability of the guanalyl cyclase C (GC-C) receptor as a target for metastatic colorectal cancer immunotherapy. GC-C is expressed exclusively in small regions of the central nervous system and on the luminal surfaces of colonic epithelial cells and induces only partial tolerance. Thus, it is an attractive target for therapeutic vaccination. This was demonstrated in mice and a Phase 1 clinical trial in humans with a GC-C-expressing adenovirus is underway.

Selected Publications

Ghosh D, Pham TD, Nanaware PP, Sengupta D, Adler LN, Li CG, He X, O'Mara ME, Kantor AB, Nguyen KD, Yang Y, Eisenlohr LC, Jensen PE, Herzenberg LA, Stern LJ, Boyd SD, Ghosn EEB, Mellins ED.: Regulation of the BCR signalosome by the class II peptide editor, H2-M, affects the development and repertoire of innate-like B cells. Cell Rep 38: 110200, Jan 2022.

Toulmin SA, Bhadiadra C, Paris AJ, Lin JH, Katzen J, Basil MC, Morrisey EE, Worthen GS, Eisenlohr LC.: Type II alveolar cell MHCII improves respiratory viral disease outcomes while exhibiting limited antigen presentation. Nat Commun 12: 3993, Jun 2021.

Yarmarkovich M, Marshall QF, Warrington JM, Premaratne R, Farrel A, Groff D, Li W, di Marco M, Runbeck E, Truong H, Toor JS, Tripathi S, Nguyen S, Shen H, Noel T, Church NL, Weiner A, Kendsersky N, Martinez D, Weisberg R, Christie M, Eisenlohr L, Bosse KR, Dimitrov DS, Stevanovic S, Sgourakis NG, Kiefel BR, Maris JM.: Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs. Nature 2021.

Lederer K, Castaño D, Gómez Atria D, Oguin TH 3rd, Wang S, Manzoni TB, Muramatsu H, Hogan MJ, Amanat F, Cherubin P, Lundgreen KA, Tam YK, Fan SHY, Eisenlohr LC, Maillard I, Weissman D, Bates P, Krammer F, Sempowski GD, Pardi N, Locci M.: SARS-CoV-2 mRNA Vaccines Foster Potent Antigen-Specific Germinal Center Responses Associated with Neutralizing Antibody Generation. Immunity 53: 1281-1295, Dec 2020.

Paris AJ, Hayer KE, Oved JH, Avgousti DC, Toulmin SA, Zepp JA, Zacharias WJ, Katzen JB, Basil MC, Kremp MM, Slamowitz AR, Jayachandran S, Sivakumar A, Dai N, Wang P, Frank DB, Eisenlohr LC, Cantu E 3rd, Beers MF, Weitzman MD, Morrisey EE, Worthen GS.: STAT3-BDNF-TrkB signalling promotes alveolar epithelial regeneration after lung injury. Nat Cell Biol 22: 1197-1210, Oct 2020.

Laczkó D, Hogan MJ, Toulmin SA, Hicks P, Lederer K, Gaudette BT, Castaño D, Amanat F, Muramatsu H, Oguin TH 3rd, Ojha A, Zhang L, Mu Z, Parks R, Manzoni TB, Roper B, Strohmeier S, Tombácz I, Arwood L, Nachbagauer R, Karikó K, Greenhouse J, Pessaint L, Porto M, Putman-Taylor T, Strasbaugh A, Campbell TA, Lin PJC, Tam YK, Sempowski GD, Farzan M, Choe H, Saunders KO, Haynes BF, Andersen H, Eisenlohr LC, Weissman D, Krammer F, Bates P, Allman D, Locci M, Pardi N.: A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice. Immunity 53: 724-732, Oct 2020.

Cosma Gabriela , Lobby Jenna L, Fay, Elizabeth J, Siciliano, Nicholas A, Langlois, Ryan A, Eisenlohr, Laurence C: Kinetically distinct processing pathways diversify the CD8+ T cell response to a single viral epitope. Proc. Nat. Acad. Sci. Aug 2020.

Forsyth, K.S., Roy, N.H., Peauroi, E., DeHaven, B.C., Wold, E.D., Hersperger, A.R., Burkhardt, J.K., Eisenlohr, L.C.: Ectromelia-encoded virulence factor C15 specifically inhibits antigen presentation to CD4+ T cells post peptide loading. PLoS Pathogens Aug 2020.

Cho Kyung-Jin, Ishido Satoshi, Eisenlohr Laurence C, Roche Paul A: Activation of Dendritic Cells Alters the Mechanism of MHC Class II Antigen Presentation to CD4 T Cells. Journal of immunology (Baltimore, Md. : 1950) 204(6): 1621-1629, Mar 2020.

Lang Jonathan F, Toulmin Sushila A, Brida Kasey L, Eisenlohr Laurence C, Davidson Beverly L: Standard screening methods underreport AAV-mediated transduction and gene editing. Nature communications 10(1): 3415, Jul 2019.

back to top
Last updated: 06/11/2022
The Trustees of the University of Pennsylvania