T follicular helper (Tfh) cells are a specialized subset of CD4⁺ T cells that play a central role in humoral immunity. They are essential for B cell activation, germinal center (GC) formation, antibody class switching, and the production of high-affinity antibodies. Within the GC microenvironment of secondary lymphoid organs, GC Tfh cells act as key regulators of B cell differentiation and antibody affinity maturation.

Our lab aims to uncover how GC Tfh cells interact with B cells after differentiating from precursor Tfh populations and how these interactions are precisely regulated. Importantly, GC Tfh cells are not a uniform population but display distinct transcriptional and functional heterogeneity. However, the molecular mechanisms that sustain or fine-tune their interactions with B cells remain poorly understood.

To address these questions, we pursue several complementary approaches:

Single-cell RNA sequencing: We analyze the transcriptional heterogeneity of GC Tfh cells to identify candidate genes that mediate their interactions with B cells. We then functionally characterize these genes to elucidate the molecular basis of GC Tfh–B cell communication.

Spatial transcriptomics & tissue imaging: We combine spatial transcriptomics with immunofluorescence-based imaging to understand how the anatomical localization of Tfh cells within the GC correlates with their gene expression and functional specialization. This work aims to define location-specific nature of Tfh cells.

Intravital microscopy (IVM): We aim to utilize IVM to visualize immune cell behavior in real time within lymphoid organs and peripheral tissues. Through this approach, we will uncover the in vivo dynamics and regulatory mechanisms of Tfh cell function and heterogeneity.

Our goal is to advance our understanding of CD4⁺ T cell-dependent humoral immunity and provide new insights for immunotherapeutic strategies. 

While vaccines have significantly reduced the global burden of infectious diseases, many current platforms fall short in inducing durable and broadly protective antibody responses—particularly against rapidly evolving viruses such as influenza and coronaviruses. Addressing this challenge requires both enhancing the magnitude and refining the quality of humoral responses.

Tfh cells play a pivotal role in driving these outcomes by promoting GC formation, B cell selection, and antibody affinity maturation. Our lab focuses on engineering vaccine strategies that optimize Tfh cell responses and guide B cell selection toward the production of broadly neutralizing antibodies (bnAbs) capable of targeting conserved viral epitopes.

Our approach integrates:

Antigen engineering: Designing antigens that preferentially engage bnAb precursors and promote their contribution to GC formation and long-term humoral immunity.

Adjuvant optimization: Engineering adjuvants to enhance Tfh differentiation and support long-lasting GC response in the context of vaccination.

mRNA-LNP platforms: Leveraging cutting-edge mRNA-LNP delivery systems to drive robust and precise immune responses.

By fine-tuning these components, we aim to promote both the scale and precision of antibody responses and ultimately inform the design of next-generation vaccines with broad and durable protection. 

T cells are central to anti-tumor immunity and key targets of cancer immunotherapy. However, in the context of persistent antigen exposure-such as within the tumor microenvironment-T cells enter a dysfunctional state known as T cell exhaustion. Exhausted T cells exhibit impaired effector function, reduced cytokine production, and poor proliferative capacity, presenting a major obstacle to effective immunotherapy. 

Our research seeks to understand and overcome T cell exhaustion through two complementary avenues:

Intrinsic mechanisms: We investigate the transcriptional and epigenetic programs that drive CD8⁺ T cell exhaustion, with the goal of identifying targets to restore their effector functions. 

Extrinsic regulation by Tfh and B cells: We are exploring how Tfh cells and B cells can modulate CD8⁺ T cell states and contribute to reprogramming exhausted T cells toward functional anti-tumor responses.

Through these efforts, we aim to develop new strategies that enhance the efficacy of cancer immunotherapies and broaden their clinical impact.