Michela Locci

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Assistant Professor of Microbiology
Department: Microbiology
Graduate Group Affiliations

Contact information
Department of Microbiology
Perelman School of Medicine, University of Pennsylvania
421 Curie Blvd, Room 351
Philadelphia, PA 19104
Office: 1-215-898-7870
Masters (Biotechnology)
University of Bologna , 2005.
Ph.D. (Immunology and Applied Biotechnology)
Tor Vergata University, PhD Thesis "Characterization of invariant NKT cell phenotype and function in Wiskott-Aldrich Syndrome (WAS) Mentor: Anna Villa MD, PhD, 2010.
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Description of Research Expertise

The production of antibodies (Abs) with high affinity and pathogen neutralization potential is crucial for preventing and fighting pathogen infection. To produce such Abs, naïve B cells are activated in response to cognate antigen and subsequently undergo rounds of somatic hypermutation and selection in germinal centers, specialized microanatomical sites in secondary lymphoid organs. This process of affinity maturation is tightly regulated by a specialized subset of CD4 T cells named T follicular helper (Tfh) cells. Our laboratory is interested in dissecting the complex biology of Tfh cells. Understanding (1) how Tfh differentiation is regulated and (2) by what means Tfh cells enable effective B cell responses are two major research goals that our group seeks to address by using a multidisciplinary approach that combines cellular and molecular immunology as well as transcriptomics:

1) Tfh cells undergo a multistage process to become fully differentiated effector cells. This sophisticated process is driven by a network of cytokines and costimulatory molecules that has been only partially elucidated. To uncover novel regulators of human Tfh differentiation, we set up a high throughput in vitro screen of a custom library of human secreted or cell surface proteins. The screen identified the cytokine activin A as a strong hit in promoting the differentiation of Tfh-like cells from human naïve CD4 T cells activated in vitro (Locci et al. Nat. Immunol., 2016). We found that activin A orchestrates the expression of multiple Tfh-associated genes, including PD-1, CXCR5 and CXCL13, in a highly specific fashion. Ongoing and future studies are aimed at dissecting the molecular mechanism by which activin A regulates human Tfh differentiation as well as the role played by activin A in Tfh cell differentiation and B cell helper function in vivo. Furthermore, additional candidates are currently being evaluated for their capacity to mold Tfh cell differentiation.

2) In germinal centers, bona fide Tfh cells regulate the survival and selection of high affinity B cells by delivering ‘help’ signals via cytokines and membrane-bound costimulatory receptors. Thus far, the functional mediators utilized by Tfh cells to provide help to germinal center B cells are poorly understood. Studies on human memory Tfh cells from peripheral blood, which are considered as the circulating counterpart of lymphoid tissue bona fide Tfh cells, revealed a high degree of functional heterogeneity in the Tfh cell population. We described the blood Th1-depleted PD-1+CXCR3- cells as the memory Tfh cell subset with the highest B cell helper capacity (Locci et al. Immunity 2013). Our group seeks to untangle the functional heterogeneity of human memory and bona fide Tfh and unmask crucial mediators of B cell help by performing single-cell transcriptional profiling coupled to functional studies.

We are accepting applications for highly motivated undergraduate/graduate students and postdoctoral fellows. Individuals with a strong background in cellular/molecular immunology or bioinformatics are encouraged to apply by submitting a CV and a cover letter by email (michela.locci@pennmedicine.upenn.edu).

Selected Publications

Castano D, Wang S, Atencio-Garcia S, Shields E, Rico MC, Sharpe H, Bustamante J, Yang E, Feng E, le Coz C, Romberg ND, Tobias JW, Utz PJ, Henrickson, Casanova JL, Bonasio R, Locci M: IL-12 drives the differentiation of human T follicular regulatory cells. Science Immunology 9(97): Epub, July 2024.

Bettini E, Chudnovskiy A, Protti G, Nakadakari-Higa S, Ceglia S, Castano D, Chiu J, Muramatsu H, Mdluli T, Abraham E, Lipinszki Z, Maillard I, Tam YK, Reboldi A, Pardi N, Spreafico R, Victra GD, Locci M: Distinct components of nucleoside-modified messenger RNA vaccines cooperate to instruct efficient germinal center responses. bioRxiv Page: Preprint, May 2024.

Haque TT, Weissler KA, Schmiechen Z, Laky K, Schwartz DM, Li J, Locci M, Turfkruyer M, Yao C, Schaughency P, Leak L, Lack J, Kanno Y, O'Shea J, Frischmeyer-Guerrerio PA.: TGFβ prevents IgE-mediated allergic disease by restraining T follicular helper 2 differentiation. Science Immunology 91(9): Epub, Jan 2024.

Proal AD, VanElzakker MB, Aleman S, Bach K, Boribong BP, Buggert M, Cherry S, Chertow DS, Davies HE, Dupont CL, Deeks S, Eimer W, Ely EW, Fasano A, Freire M, Geng LN, Griffin D, Henrich TJ, Iwasaki A, Izquierdo-Garcia D, Locci M, Mehandru S, Painter M, Peluso MJ, Pretorius E, Price DA, Putrino D, Scheuermann RH, Tan GS, Tanzi RE, VanBrocklin HF, Yonker L, Wherry EJ. : SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC): A review of the evidence and directions for future research. Nat Immunol 24(10): 1778, Oct 2023.

Pine M, Arora G, Hart TM, Bettini E, Gaudette BT, Muramatsu H, Tombácz I, Kambayashi T, Tam YK, Brisson D, Allman D, Locci M, Weissman D, Fikrig E, Pardi N.: Development of an mRNA-lipid nanoparticle vaccine against Lyme disease. Molecular Therapy 31(9): 2702-2714, Sept 2023.

Palin A, Alter G, Crotty S, Ellebedy A, Lane C, Lee F, Locci M, Malaspina A, Mallia C, McElrath JM, Pulendran B, Singh A, D’Souza P. : The Persistence of Memory: Defining, Engineering, and Measuring Vaccine Durability. Nat Immunol 23(12), Dec 2022.

Bettini E, Lederer K, Sharpe H, Kaminiski M, Jones L, Locci M. : Assessment of human germinal center responses to SARS-CoV-2 vaccination via a combined fine needle aspiration and spectral flow cytometry approach. STAR Protoc 3(4), Dec 2022.

Lederer K, Bettini E, Parvathaneni K, Painter MM, Agarwal D, Lundgreen KA, Weirick M, Muralidharan K, Castaño D, Goel RR, Xu X, Drapeau EM, Gouma S, Ort JT, Awofolaju M, Greenplate AR, Le Coz C, Romberg N, Trofe-Clark J, Malat G, Jones L, Rosen M, Weiskopf D, Sette A, Besharatian B, Kaminiski M, Hensley SE, Bates P, Wherry EJ, Naji A*, Bhoj V*, Locci M*. * co-corresponding authors: Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals. Cell 185(6), Mar 2022.

Alameh MG, Tombácz I, Bettini E, Lederer K, Sittplangkoon C, Wilmore JR, Gaudette BT, Soliman O, Pine M, Hicks P, Manzoni TB, Knox J, Johnson JL, Laczkó D, Muramatsu H, Davis B, Meng W, Rosenfeld AM, Strohmeier S, Lin PJC, Mui BL, Tam YK, Karikó K, Jacquet A, Krammer F, Bates P, Cancro MP, Weissman D, Luning Prak E, Allman D, Locci M*, Pardi N*. * co-corresponding authors: Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses. Immunity 54(12), Dec 2021.

Lederer K, Parvathaneni K, Painter MM, Bettini E, Agarwal D, Lundgreen KA, Weirick M, Goel RR, Xu X, Drapeau EM, Gouma S, Greenplate AR, Coz CL, Romberg N, Jones L, Rosen M, Besharatian B, Kaminiski M, Weiskopf D, Sette A, Hensley SE, Bates P, Wherry EJ, Naji A*, Bhoj V*, Locci M*. * co-corresponding authors: Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals. medRxiv Sept 2021.

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Last updated: 07/11/2024
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