Michela Locci, Ph.D.
Perelman School of Medicine, University of Pennsylvania
421 Curie Blvd, Room 351
Philadelphia, PA 19104
Alma Mater Studiorum University, 2005.
Ph.D. (Immunology and Applied Biotechnology)
Tor Vergata University, 2010.
Description of Research ExpertiseThe 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 (firstname.lastname@example.org).
Selected PublicationsWing JB, Kitagawa Y, Locci M, Hume H, Tay C, Morita T, Kidani Y, Mikulski Z, Matsuda K, Inoue T, Kurosaki T, Crotty S, Coban C, Ohkura N, Sakaguchi S.: A distinct subset of CD25 negative T-follicular regulatory cells localizes in the germinal centers. PNAS 114(31), August 2017.
Schulten V, Tripple V, Seumois G, Qian Y, Scheuermann RH, Fu Z, Locci M, Rosales S, Vijayanand P, Sette A, Alam R, Crotty S, Peters B.: Allergen-specific immunotherapy modulates the balance of circulating Tfh and Tfr cells. J Allergy Clin Immunol.(17), pii: S0091-6749, May 2017.
Havenar-Daughton C, Carnathan DG, Torrents de la Peña A, Pauthner M, Briney B, Reiss SM, Wood JS, Kaushik K, van Gils MJ, Rosales S, van der Woude P, Locci M, Le KM, de Taeye SW, Sok D, Rasheed Mohammed AU, Huang J, Gumber S, Garcia A, Kasturi SP, Pulendran B, Moore JP, Ahmed R, Seumois G, Burton DR, Sanders RW, Silvestri G, Crotty S.: Direct probing of germinal center responses reveals immunological features and bottlenecks for neutralizing antibody responses to HIV Env trimer. Cell Reports 17(9): 2195-2209, November 2016.
Locci M, Wu J, Arumemi F, Mikulski Z, Dahlberg C, Miller AT, Crotty S: Activin A programs the differentiation of human Tfh cells. Nature Immunology 17(8): 976-84, August 2016.
Hu JK, Crampton JC, Locci M, Crotty S: CRISPR-mediated Slamdf1 Slamf5 Slamf6 triple gene disruption reveals NKT cell defects but not T follicular helper cell defects. PLoS One 11(5), May 2016.
Cubas R, van Grevenynge J, Willis S, Kardava L, Santich BH, Buckner CM, Muir R, Tardif V, Nichols C, Procopio F, He Z, Metcalf T, Chneim K, Locci M, Ancuta P, Routy JP, Trautmann L, Li Y, McDermott AB, Koup RA, Petrovas C, Migueles SA, Connors M, Tomaras GD, Moir S, Crotty S, Haddad EK: Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection. J. Immunology 195(12): 5625-36, Decemeber 2015.
Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn CL, Su LF, Cubas R, Davis MM, Sette A, Haddad EK, International AIDS Vaccine Initiative Protocol C investigators, Poignard P, Crotty S: Human Circulating PD-1+ CXCR3-CXCR5+ Memory Tfh Cells Are Highly Functional and Correlate with Broadly Neutralizing HIV Antibody Responses. Immunity 39(4): 758-69, October 2013.
Catucci M, Prete F, Bosticardo M, castiello MC, Draghici E, Locci M, Roncarolo MG, Aiuti A, Benvenuti F, Villa A: Dendritic cell functional improvement in a preclinical model of lentiviral-mediated gene therapy for Wiskott-Aldrich syndrome. Gene Therapy 19(12): 1150-58, December 2012.
Kageyama R, Cannons JL, Zhao F, Yusuf I, Lao C, Locci M, Schwartzberg PL, Crotty S: The receptor Ly108 functions as a SAP adaptor-dependent on-off switch for T cell help to B cells and NKT cell development. Immunity 36(6): 986-1002, June 2012.
Kroenke MA, Eto D, Locci M, Cho M, Davidson T, Haddad EK, Crotty S: Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J. Immunology 188(8): 3734-44, April 2012.