Applied Germinal Center Biology in Human Health and Disease:


CD4 T Follicular Helper (Tfh) cells are an integral component of the adaptive immune system that coordinate antibody responses and establish antigenic memory. Tfh activation is vitally important to defend against pathogens and is a central goal of vaccination. Dysregulated Tfh activation is also implicated in autoimmune and allergenic diseases. Despite the significance of Tfh in human health and disease, our understanding of Tfh activation and function primarily derives from mouse models. In humans, Tfh have typically been profiled in blood due to sample availability. However, Tfh in blood are phenotypically disparate from Tfh at their primary site of activity in lymphoid tissue germinal centers (GC). Fundamental aspects of human Tfh biology remain unclear, including gene expression programs that enable vital Tfh functions within the GC compartment. 

GCs are found in secondary lymphoid organs including lymph nodes, tonsil, Peyer's patches, and the spleen. Within the GC, Tfh coordinate differentiation and affinity maturation of B cells. In the Vella Lab, we use human tonsil as a model lymphoid tissue for studying interactions between Tfh and B cells in the GC. To delineate mechanisms underlying GC evolution, we apply single-cell multiomics, spatial transcriptomics, spectral flow cytometry, and gene targeting approaches. This high-dimensional approach aims to identify and validate novel molecular mechanisms in GC biology for diagnostic monitoring and therapeutic targeting in human health and disease.


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Immune Reconstitution: Vaccine Readiness, GVHD, Control of Opportunistic/latent infections:

Hematopoietic cell transplantation (HCT) offers a potential cure for many hematologic malignancies and immune disorders. However, the complex immune dynamics post transplantation can lead to serious complications, including graft-versus-host disease (GVHD) and delayed immune reconstitution, which impact long-term quality of patient life.Another major focus of our lab is on immune reconstitution and vaccine readiness following HCT. Patients often face prolonged immune deficiency due to lymphocyte depletion and immune dysregulation, making them susceptible to infections and limiting the efficacy of vaccinations.

We are particularly interested in:

1. Tracking the recovery of T and B cell populations at the single-cell level.

2. Evaluating vaccine-induced immune responses, especially to SARS-CoV-2 and influenza.

3. Identifying correlates of protection in patients post-transplant to guide timing and prioritization of vaccination strategies.

By integrating clinical data with high-resolution immune profiling, we aim to personalize post-transplant vaccination strategies, improve protection against infection, and enhance overall recovery.

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HIV-1 Reservoir Biology and the Development of New Single Cell Techniques:

HIV-1 remains an ongoing global public health issue owing to the ability of HIV-1 to exist in a state that is impervious to host immunity and antiretroviral therapy (ART), the current standard of care for HIV-1. This form of HIV-1, known as proviral latency, allows the virus to persist such that when people with HIV-1 (PWH) on ART discontinue their medications, viral replication returns in a matter of weeks, thus necessitating a lifetime of ART in order to maintain viral suppression (having an undetectable viral load). These infected cells that contribute to rebound viremia upon ART cessation are called 'reservoir cells' and comprise the 'latent reservoir', which represents the principle barrier to a lasting cure to HIV-1. As a lab, we are interested in the immunobiology of these reservoir cells, asking what cellular features may endow this population of cells (primarily CD4+ T lymphocytes) to restrain viral expression and to persist durably despite cell turnover. Because HIV-1 is a retrovirus, its replication cycle involves integration of its genome into human DNA, from which viral transcripts can be synthesized using host transcriptional machinery. We seek to capitalize on this biology using single-cell multimodal techniques (pairing of RNAseq and ATACseq from the same individual cells) to (1) characterize the infection status of cells (based on the presence of HIV-1 nucleic acids) and then (2) interrogate the cellular programs that may contribute to reservoir cells' ability to evade host immune responses and maintain pro-survival states. Identification of cellular pathways that favor virus quiescence while engendering a long-lived state could represent druggable targets for HIV-1 curative efforts that seek to reduce the size of the latent reservoir. In combination with immunotherapuetic interventions that boost host anti-HIV-1 immunity, pharmacologic modulation of reservoir cells latency and susceptibility to cell death offers hope to attain ART-free lives for PWH.  













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