Research in the Sage Lab focuses on understanding how the immune system regulates B cell responses and antibody production. Antibodies clear harmful pathogens and mediate protection elicited by vaccination. However, dysregulation of antibody responses can result in systemic autoimmunity. Therefore, the immune system has developed intricate regulatory machinery to ensure that antibody responses are both appropriate and tightly controlled. By understanding these pathways, therapeutics can be developed that can optimize vaccine responses and treat systemic autoimmunity. The vast majority of antibody responses originate from a highly organized process called the germinal center reaction. In this reaction, T follicular helper (Tfh) cells interact with B cells to stimulate antibody responses. At the same time, T follicular regulatory (Tfr) cells interact with B cells and inhibit antibody responses. Therefore, the outcome of humoral immunity is a delicate balance between stimulatory Tfh and inhibitory Tfr function.
The lab is elucidating immunoregulation of B cell responses using three approaches:
How are Tfh and Tfr cells transcriptionally programmed to regulate B cell responses? By understanding the machinery Tfh and Tfr cells use to perform their functions, we can develop novel therapeutics to modulate these cells. We use genomics strategies (bulk RNAseq, single cell RNAseq, ATAC-seq) and functional assays to uncover pathways essential for the stimulation or regulation of B cell responses. These studies have helped us understand how inhibitory receptors such as PD-1 and CTLA-4, as well as immunometabolism, have multifaceted roles in modulating antibody responses. In addition, we recently elucidated the Tfr transcriptional program, and how alterations in this program can lead to cellular dysfunction and altered B cell responses (Hou J. Exp. Med. 2019).
How do Tfh and Tfr cell subsets control long term B cell responses? By understanding how Tfh and Tfr cells contribute to B cell responses, strategies can be developed to augment vaccines and limit viral infection. We use novel genetic mouse models to perturb Tfh and Tfr cells to understand how these cell types regulate B cell responses at distinct stages during vaccination and infection. These studies allow us to elucidate strategies to enhance vaccine effectiveness.
How do alterations in Tfh and Tfr cells contribute to disease? Dysregulation of Tfh and Tfr cells are thought to lead to progression of autoimmune diseases. We use a combination of novel genetic mouse models and human clinical samples to study the contribution of Tfh and Tfr cells to a number of disease states (such as multiple sclerosis, lupus, transplant rejection and allergic inflammation). These studies allow us to determine how targeting Tfh and Tfr cells can be used clinically to alleviate disease.
Transplant Research Center Renal Division
221 Longwood Ave, EBRC302
Boston, MA 02115