Cell Migration Dynamics and Intercellular Communications Underlying Immunity

Background: The immune system is composed of multiple cell types that are distributed in lymphoid and non-lymphoid tissues throughout the body. Understanding how immune cells help maintain tissues in a healthy metabolic state and ensure homeostasis with commensals while being able to respond rapidly to foreign invaders or malignant self requires a precise understanding of how they position in tissues and how they communicate. This research challenge is strikingly exemplified during humoral immune responses, where rare antigen-specific B and T lymphocytes must first encounter antigen and then interact with each other to mount an antibody response. Another example is the continual surveillance of epithelial surfaces by innate lymphocytes. There is also evidence that the success of current immunotherapies for cancer is tightly correlated with the efficiency of immune cell access to the tumor microenvironment.

Major Goals:

• Decipher the guidance cue codes controlling leukocyte migration and interaction events during tissue surveillance and immune response
• Visualize immune response dynamics using advanced imaging and cell engineering approaches
• Define the selection mechanisms for antibody affinity maturation and those that help prevent autoantibody production
• Characterize the cellular dynamics underlying mucosal immune responses
  

On-going Research:

Chemokines and Lipid Mediators as Tissue Organizers: Chemokines are small secreted chemoattractive proteins that signal via heterotrimeric G-protein coupled receptors (GPCRs). We have demonstrated that several chemokines are expressed in lymphoid organs and function in guiding lymphocyte migration. More recently we identified a role for an intercellular signaling lipid, the oxysterol 7a,25-dihydroxycholesterol, in guiding B cell, dendritic cell (DC) and T follicular helper (Tfh) cell movements and in supporting humoral immune responses (Fig. 1). We have also determined how the oxysterol 25-hydroxycholesterol controls IL1-family cytokine production by macrophages. An important thrust of our ongoing work is a discovery program to identify unaccounted for extracellular cues that control multiple other immune cell migration, interaction and communication processes.