Research Area
Our research is focused on the biology of T follicular helper (Tfh) cells and the regulation of germinal center (GC) responses following vaccination and viral infection. Currently, major efforts in the Locci lab are aimed at shedding light on the: 1)Immunological mechanisms of mRNA vaccines. We seek to uncover how the immune system senses the mRNA and the lipid nanoparticle (LNP) components of this vaccine platform, and what are the signals induced by mRNA-LNP that guide the differentiation of Tfh cells in the GC. 2) Mechanisms that regulate the durability of antibody responses elicited by mRNA-LNP vaccines. We are dissecting the signals delivered by Tfh cells to GC B cells that guide the differentiation of long-lived plasma cells. 3) Pathogenesis of Long-COVID. By using a fine needle aspirate approach, we are characterizing the GC responses to SARS-CoV-2 infection in lymph nodes of Long-COVID patients and COVID-19 convalescents.
Team Description
It takes a village to do great science. This is the Locci lab village, a team of talented, smart and motivated young scientists with a strong passion for germinal center biology and vaccines/viral infections. Remember these faces, they will uncover the immunological mechanisms of mRNA vaccines and unveil a possible germinal center contribution to the pathogenesis of Long-COVID.
Team Members
Team Show
Publications
1.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. 2022 Dec 16;3(4):101840. doi: 10.1016/j.xpro.2022.101840. Epub 2022 Oct 24. PMID: 36595931
2.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. 2022 Dec;23(12):1665-1668. doi: 10.1038/s41590-022-01359-z. PMID: 36456737
3.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. Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals.Cell. 2022 Mar 17;185(6):1008-1024.e15. doi: 10.1016/j.cell.2022.01.027. Epub 2022 Feb 2. PMID: 35202565
4.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 authorsLipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses.Immunity. 2021 Dec 14;54(12):2877-2892.e7. doi: 10.1016/j.immuni.2021.11.001. Epub 2021 Nov 4. PMID: 34852217
5.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. 2021 Sep 21:2021.09.16.21263686. doi: 10.1101/2021.09.16.21263686. Preprint. PMID: 34580676
6.Bettini E, Locci M.SARS-CoV-2 mRNA Vaccines: Immunological Mechanism and Beyond.Vaccines (Basel). 2021 Feb 12;9(2):147. doi: 10.3390/vaccines9020147. PMID: 33673048.
7.Lu Y, Jiang R, Freyn AW, Wang J, Strohmeier S, Lederer K, Locci M, Zhao H, Angeletti D, O'Connor KC, Kleinstein SH, Nachbagauer R, Craft J.CD4+ follicular regulatory T cells optimize the influenza virus-specific B cell response.J Exp Med. 2021 Mar 1;218(3):e20200547. doi: 10.1084/jem.20200547. PMID: 33326020
8.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. 2020 Dec 15;53(6):1281-1295.e5. doi: 10.1016/j.immuni.2020.11.009. Epub 2020 Nov 21. PubMed PMID: 33296685; PubMed Central PMCID: PMC7680029.
9.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. 2020 Jul 30;53(4):724-732.e7. Online ahead of print. PMID: 32783919.
10.Carnathan DG, Kaushik K, Ellebedy A, Enemuo CA, Gebru EH, Dhadvai P, Rasheed MAU, Pauthner MG, Ozorowski G, Ahmed R, Burton D, Ward AB, Silvestri G, Crotty S, Locci M.Harnessing Activin A Adjuvanticity to Promote Antibody Responses to BG505 HIV Envelope Trimers.Frontiers in Immunology. 2020. Jun 16;11:1213. doi: 10.3389/fimmu.2020.01213. eCollection 2020. PMID: 32612608
11.Wing 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.Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):E6400-E6409. doi: 10.1073/pnas.1705551114. Epub 2017 Jul 11.
12.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. 2017 May 12; pii: S0091-6749(17)30756-X. doi: 10.1016/j.jaci.2017.04.032.
13.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. 2016 Nov 22;17(9):2195-2209.
14.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. 2016 Aug;17(8):976-84.
15.Hu JK, Crampton JC, Locci M, Crotty S.CRISPR-mediated Slamf1/ Slamf5/ Slamf6/ triple gene disruption reveals NKT cell defects but not T follicular helper cell defects.PLoS One. 2016 May 25;11(5): e0156074.
16.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, Ghneim 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. 2015 Dec 15;195(12):5625-36.
17.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. 2013 Oct 17;39(4):758-69.
18.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. 2012 Jun 29;36(6):986-1002.
19.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, 2012 April 15;188(8):3734-44.
20.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. 2012 Dec;19(12):1150-8.
21.Bosticardo M, Draghici E, Schena F, Sauer AV, Fontana E, Castiello MC, Catucci M, Locci M, Naldini L, Aiuti A, Roncarolo MG, Poliani PL, Traggiai E, Villa A.Lentiviral-mediated gene therapy leads to improvement of B-cell functionality in a murine model of Wiskott-Aldrich syndrome.J Allergy Clin Immunology. 2011 Jun;127(6):1376-84.
22.Locci M, Draghici E, Marangoni F, Bosticardo M, Catucci M, Aiuti A, Cancrini C, Marodi L, Espanol T, Bredius RG, Thrasher AJ, Schulz A, Litzman J, Roncarolo MG, Casorati G, Dellabona P, Villa A.The Wiskott-Aldrich syndrome protein is required for iNKT cell maturation and function.J Experimental Medicine (JEM). 2009 Apr 13;206(4):735-42.
23.Marangoni F, Bosticardo M, Charrier S, Draghici E, Locci M, Scaramuzza S, Panaroni C, Ponzoni M, Sanvito F, Doglioni C, Liabeuf M, Gjata B, Montus M, Siminovitch K, Aiuti A, Naldini L, Dupré L, Roncarolo MG, Galy A, Villa A.Evidence for long-term efficacy and safety of gene therapy for Wiskott-Aldrich syndrome in preclinical models.Molecular Therapy. 2009 Jun;17(6):1073-82.