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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

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 infection and protein immunization, high parameter flow cytometry and high-throughput screening approaches to uncover novel regulators of human and murine Tfh cell differentiation. 

Tfh Cell Function

Fully mature Tfh cells are located in germinal centers, where they 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 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. 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. 

Tfh Biology in Infectious and Autoimmune Diseases

Our laboratory is interested in unravelling the dysregulated pathways that lead to dysfunctional/aberrant Tfh differentiation and B cell helper function in diseases such as chronic infections (HIV) and autoimmunity (Rheumatoid Arthritis and Type I Diabetes). We study the phenotype, gene program 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 Tfh cells to the pathogenesis of multiple diseases characterized by altered Ab responses. 

 

SELECTED

PUBLICATIONS

Fig. 1
Fig. 1

A single immunization with SARS-CoV-2 mRNA vaccines results in robust GC B cell responses.

Fig. 2
Fig. 2

SARS-CoV-2 mRNA vaccines elicit strong antigen-specific GC B cell responses.

Fig. 7
Fig. 7

A booster immunization with a SARS-CoV-2 mRNA vaccine induces robust 703 secondary GCs and nAbs.

Fig. 1
Fig. 1

A single immunization with SARS-CoV-2 mRNA vaccines results in robust GC B cell responses.

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Fig. 1
Fig. 1

Activin A modulated generation of BG505 SOSIP Env trimer-specific Abs.

Fig. 2
Fig. 2

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.

Figure 4
Figure 4

Modulation of TFH and TFR cells by activin A. T cell populations were analyzed by flow cytometry in iliac lymph nodes at week 14.

Fig. 1
Fig. 1

Activin A modulated generation of BG505 SOSIP Env trimer-specific Abs.

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Fig.1
Fig.1

High throughput screening identifies activin A as a potent regulator of human TFH cell differentiation.

Fig.2
Fig.2

INHBA is present in sites relevant for TFH cell differentiation and can be produced by myeloid cells.

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Fig.8

Activin A activity is mediated by an ALK4-SMAD2/3 pathway.

Fig.1
Fig.1

High throughput screening identifies activin A as a potent regulator of human TFH cell differentiation.

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Activin A programs human TFH cell differentiation
Locci M, Wu J, Arumemi F, et al. (Nat Immunol. 2016)
Fig.1
Fig.1

Blood total CXCR5+CD4+ T cells fail to correlate with HIV bnAb development.

Fig.2
Fig.2

Human blood PD-1+CXCR5+CD4+ T cells.

Fig.6
Fig.6

Highly functional PD-1+CXCR3−CXCR5+CD4+ T cells are associated with HIV bnAb development.

Fig.1
Fig.1

Blood total CXCR5+CD4+ T cells fail to correlate with HIV bnAb development.

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Fig. 1
Fig. 1

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.

Fig. 2
Fig. 2

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.

Fig. 7
Fig. 7

Human tonsillar Tfr cells. (A–C) Fresh human tonsils were obtained from the National Disease Resource Interchange.

Fig. 1
Fig. 1

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.

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Fig.1
Fig.1

Generation of autologous neutralizing antibodies by immunization with BG505 SOSIP.v5.2.

Fig.2
Fig.2

FNAs monitor GC activity in draining lymph nodes.

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Fig.7

GC Tfh cell quality is associated with autologous nAb.

Fig.1
Fig.1

Generation of autologous neutralizing antibodies by immunization with BG505 SOSIP.v5.2.

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CONTACTS

Location

Department of Microbiology
Perelman School of Medicine

University of Pennsylvania

421 Curie Blvd, BRB 343
Philadelphia, PA 19104

Join Us

We are accepting applications for highly motivated 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.​

News
  • 11/21/2020: Our new article published in Immunity is now live: SARS-CoV-2 mRNA vaccines foster potent antigen-specific germinal center responses associated with neutralizing antibody generation.

  • 10/12/2020: Welcome Emily Bettini, a PhD student in Immunology Graduate Group, joining the lab.