Welcome to the Locci lab
ABOUT
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.
RESEARCH
Tfh Cell Differentiation and Function
Differentiation. The differentiation of Tfh cells is a complex multi-step, multi-factorial process that has not been fully elucidated yet. Our group is interested in characterizing the stimuli required for this process. We utilize in vitro differentiation assays with human primary naive CD4 T cells, in vivo mouse models of viral infection and mRNA vaccination, high parameter spectral flow cytometry and single-cell transcriptomics to uncover novel regulators of human and murine Tfh cell differentiation. Current projects include the study of cytokines and long noncoding RNA in Tfh cell differentiation.
Function. Fully mature Tfh cells provide ‘help’ to B cells 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 revealed a high degree of functional heterogeneity in the Tfh cell population. 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 gene editing and functional studies.
Regulation of Germinal Center responses by mRNA vaccines
Messenger RNA (mRNA) vaccines are a potent vaccine platform capable of conferring elevated protection against viral infections. Our group has demonstrated that SARS-CoV-2-encoding mRNA vaccines elicit robust Tfh and germinal center (GC) B cell responses in mice. By adopting a fine needle aspiration approach to probe GCs in vaccine draining lymph nodes, we have also uncovered a powerful induction of GC responses, associated with the production of neutralizing antibodies and memory B cells in humans. Current efforts are aimed at dissecting the mechanism by which mRNA vaccines drive such robust GC responses. By deploying cutting edge techniques and custom mRNA-lipid nanoparticle (LNP) reagents, we seek to deconvolute the sensing mechanism and the signals triggered by mRNA-LNP that, in turn, promote the differentiation of Tfh cells. We are also investigating the functional flavor of Tfh cells induced by mRNA vaccines in comparison to other vaccine platforms. Mechanistic studies are being performed in selected mouse models and, where possible, corroborated in human samples collected via fine needle aspiration.
Tfh Biology in Infectious and Autoimmune Diseases
Our laboratory is interested in unraveling the dysregulated pathways that lead to dysfunctional/aberrant Tfh differentiation and B cell helper function in infectious diseases such as post-acute sequelae of COVID-19 (PASC). We study the phenotype, transcriptional profile and function of primary human Tfh cells by high parameter flow cytometry (25 colors), single cell transcriptomics and in vitro functional assays to unveil the contribution of aberrant Tfh cells and B cell responses to the pathogenesis of PASC. We are also interested in understanding what causes altered Tfh cell responses in autoimmune diseases characterized by autoantibody production, including Rheumatoid Arthritis (RA) and Type I Diabetes. We have recently identified a cytokine playing a role in the aberrant Tfh cells responses associated with RA, and we are performing preclinical studies in mouse models where such cytokine is targeted for the therapeutic modulation of RA.
SELECTED
PUBLICATIONS
GC B cell responses to SARS-CoV-2 mRNA vaccines are detected in ipsilateral but 556 not in contralateral LNs of immunocompetent individuals.
GC B cell responses to SARS-CoV-2 mRNA vaccines are detected in ipsilateral but 556 not in contralateral LNs of immunocompetent individuals.
Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals
Lederer K, et al. (Cell. 2022)
LNP-adjuvanted HA mRNA and protein subunit vaccines induce durable, protective humoral responses
LNP-adjuvanted HA mRNA and protein subunit vaccines induce durable, protective humoral responses
Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses
Alameh M, Tombácz I, Bettini E, et al. (Immunity. 2021)
A single immunization with SARS-CoV-2 mRNA vaccines results in robust GC B cell responses.
SARS-CoV-2 mRNA vaccines elicit strong antigen-specific GC B cell responses.
A booster immunization with a SARS-CoV-2 mRNA vaccine induces robust 703 secondary GCs and nAbs.
A single immunization with SARS-CoV-2 mRNA vaccines results in robust GC B cell responses.
SARS-CoV-2 mRNA vaccines foster potent antigen-specific germinal center responses associated with neutralizing antibody generation
Lederer K, Castano D, et al. (Immunity. 2020)
Activin A modulated generation of BG505 SOSIP Env trimer-specific Abs.
Activin A's regulation of bone marrow Ab-secreting cells. Bone marrow Env trimer-specific IgG secreting cells were measured by ELISPOT at the necropsy time point.
Modulation of TFH and TFR cells by activin A. T cell populations were analyzed by flow cytometry in iliac lymph nodes at week 14.
Activin A modulated generation of BG505 SOSIP Env trimer-specific Abs.
Harnessing Activin A adjuvanticity to promote antibody responses to BG505 HIV envelope trimers
Carnathan DG, et al. (Front. Immunol. 2020)
High throughput screening identifies activin A as a potent regulator of human TFH cell differentiation.
INHBA is present in sites relevant for TFH cell differentiation and can be produced by myeloid cells.
Activin A activity is mediated by an ALK4-SMAD2/3 pathway.
High throughput screening identifies activin A as a potent regulator of human TFH cell differentiation.
Activin A programs human TFH cell differentiation
Locci M, Wu J, Arumemi F, et al. (Nat Immunol. 2016)
Blood total CXCR5+CD4+ T cells fail to correlate with HIV bnAb development.
Human blood PD-1+CXCR5+CD4+ T cells.
Highly functional PD-1+CXCR3−CXCR5+CD4+ T cells are associated with HIV bnAb development.
Blood total CXCR5+CD4+ T cells fail to correlate with HIV bnAb development.
Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses
Locci M, Havenar-Daughton C, Landais E, et al. (Immunity. 2013)
Identification of CD25− Tfr cells. Mice were vaccinated s.c. with 100 μg of NP-Ova (Biosearch) in alum, and draining LNs (dLNs) or Peyer’s patches were taken at day 7 or the indicated time.
Protein expression profile of CD25− Tfr cells. Mice were vaccinated s.c. with 100 μg of NP-Ova in alum, and dLNs were taken at day 7 or day 14.
Human tonsillar Tfr cells. (A–C) Fresh human tonsils were obtained from the National Disease Resource Interchange.
Identification of CD25− Tfr cells. Mice were vaccinated s.c. with 100 μg of NP-Ova (Biosearch) in alum, and draining LNs (dLNs) or Peyer’s patches were taken at day 7 or the indicated time.
A distinct subpopulation of CD25− T-follicular regulatory cells localizes in the germinal centers
Wing JB, Kitagawa Y, Locci M, et al. (PNAS. 2017)
Generation of autologous neutralizing antibodies by immunization with BG505 SOSIP.v5.2.
FNAs monitor GC activity in draining lymph nodes.
GC Tfh cell quality is associated with autologous nAb.
Generation of autologous neutralizing antibodies by immunization with BG505 SOSIP.v5.2.
Direct probing of germinal center responses reveals immunological features and bottlenecks for neutralizing antibody responses to HIV Env trimer
Havenar-Daughton C, Carnathan DG, Locci M, et al. (Cell Rep. 2016)
CONTACTS
Location
Department of Microbiology
Perelman School of Medicine
University of Pennsylvania
421 Curie Blvd, BRB 343
Philadelphia, PA 19104
News
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02/01/2022: Our new article published in Cell is now live: Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals
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01/10/2022: Welcome Hannah Sharpe joining the lab as a postdoctoral fellow.
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11/04/2021: Our new article published in Immunity is now live: Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses