Welcome to the Locci lab
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.
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.
Identification of CD25− Tfr cells. Mice were vaccinated s.c. and i.p. with 100 μg of NP-Ova in alum, and dLNs, spleens (Spl), or Peyer’s patches (PP) were taken at day 7 or the indicated time.
Human tonsillar Tfr cells. (A–C) Fresh human tonsils were obtained from the National Disease Resource Interchange.
INHBA is present in sites relevant for TFH cell differentiation and can be produced by myeloid cells.
Direct probing of germinal center responses reveals immunological features and bottlenecks for neutralizing antibody responses to HIV Env trimer
Havenar-Daughton C, Carnathan DG, Torrents de la Peña A, Pauthner M, Briney B, Reiss SM, Wood JS, Kaushik K, van Gils MJ, Rosales SL, van der Woude P, Locci M, et al. (Cell Rep. 2016)
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)
Department of Microbiology
Perelman School of Medicine
University of Pennsylvania
421 Curie Blvd
Philadelphia, PA 19104
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.
11/01/2019: Welcome Jimin Son joining the lab as a postdoctoral fellow.
09/03/2019: Welcome Kari Ackerson joining the lab as a research specialist.
01/07/2019: Welcome Diana Castano joining the lab as a visiting professor.
11/14/2018: Michela received the W.W. Smith Charitable Trust Award for AIDS research.
10/05/2018: Welcome Madhura Mukhopadhyay joining the lab as a postdoctoral fellow.
7/12/2018: Welcome Sidney Wang joining the lab as a research specialist.
4/2/2018: Welcome Katlyn Lederer joining the lab as a research specialist.
1/22/2018: The lab has opened and dynamically developed.