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.
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.
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)
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, Locci M, et al. (Cell Rep. 2016)
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.
06/16/2020: Our new article published in Frontiers Immunology is now live: Harnessing Activin A Adjuvanticity to Promote Antibody Responses to BG505 HIV Envelope Trimers.
06/01/2020: Congratulations to Jimin Son being selected as a recipient of Postdoctoral Fellowship Program granted by National Research Foundation of Korea.
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.