Cell Migration and Interaction Dynamics Underlying Innate and Adaptive Immunity
Background: The rapid production of antibodies is critical for host defense against pathogens. Reciprocally, antibody responses against self-components are a cause of autoimmune disease. To mount antibody responses, antigen-specific B and T cells that may be as rare as 1 in 100,000 cells must first encounter the antigen and then interact with each other. These encounters occur within lymphoid organs - lymph nodes, spleen, and mucosal lymphoid tissues - but the mechanisms that control immune cell migration and that promote interactions between rare antigen-specific cells are far from understood. Similar challenges exist in understanding the cell migration and interaction dynamics needed for immune defenses at barrier surfaces.
Major goals: (i) decipher the guidance cue code controlling leukocyte migration and interactions during immune responses; (ii) characterize selection events required for induction of high affinity antibodies; (iii) define the dynamics of antigen encounter and immune responses at epithelial surfaces.
Chemokines and lipid mediators as lymphoid 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. We have also identified roles for lipid mediators, including an oxysterol, in guiding cell movements necessary for mounting dendritic cell- and T cell-dependent B cell responses. Transgenic and gene knockout experiments in mice are further defining the organizing functions of these guidance factors. Efforts are ongoing using RNAseq, CRISPR/Cas9 knockdown and retroviral over-expression approaches to test the role of novel guidance factors in promoting cell interactions during innate and adaptive immune responses. Based on our work so far, groups in industry are developing small molecule inhibitors of lymphoid chemoattractant receptors to be tested as modulators of the immune response.
Lymphocyte Egress and the role of S1P: A lot is known about how cells get into tissues from blood, but much less is understood about how they get out. Yet they must get out to mediate their effector function at sites of infection or autoimmune inflammation. In work over the last 10 years we established that the circulatory lipid, sphingosine-1-phosphate (S1P), is critical for this process. Like chemokines, S1P signals via GPCRs, and we found that if lymphocytes lack one of the five S1P receptors, S1PR1, they are unable to leave the thymus or peripheral lymphoid organs. The compound FTY720 disrupts the function of this receptor and inhibits lymphocyte egress. FTY720 (Fingolimod) was FDA approved in 2010 as a treatment for multiple sclerosis. On-going studies, involving molecular, genetic and imaging approaches, are aimed at defining how this GPCR instructs lymphocytes to exit lymphoid organs. Findings from this work are likely to point to new therapeutic targets for inhibition of unwanted immune responses.
Affinity Maturation and the Germinal Center response: Although first identified in the 1800's, the inner workings of the germinal center - the site of antibody affinity maturation - are still poorly defined. We have found a role for chemokines in organizing the structure into light and dark zones. Using 2-photon microscopy and real-time imaging of intact lymph nodes we have begun to characterize B and T cell migration and interaction dynamics during the selection events associated with this tightly regulated response. In ongoing work we combine perturbations in organizing molecules with methods to measure affinity maturation and 2-photon microscopy-based imaging approaches to further define how selection of high affinity clones - and elimination of low affinity and autoreactive clones - occurs. This work has direct implications for methods to improve vaccine design.
Barrier Immunity: IgA is a major antibody isotype made at mucosal surfaces and it functions to shape the commensal populations and to protect from gut pathogens. We are studying how B cells encounter and mount responses against mucosal antigens. We are also interested in understanding how chronic mucosal antigen exposure drives sustained germinal center responses and sometimes leads to lymphomagenesis. As well as IgA, the intestine and skin contain large numbers of innate-like lymphocytes that help maintain tissue homeostasis and barrier immunity. In ongoing work, we are studying the migration and response dynamics of innate-like lymphocytes at epithelial surfaces.