Daniel Lingwood, Ph.D.
Ragon Institute of MGH, MIT and Harvard, Mass General Research Institute
Assistant Professor of Medicine
Harvard Medical School
Medicine-Ragon Institute, Massachusetts General Hospital
|PhD Max Plank Institute for Molecular Cell Biology and Genetics (MPI-CBG) 2009|
The mechanism by which the germline B cell receptor (BCR) engages antigen prior to development of immunological memory is not well understood. New antigen-specific BCR sequences can arise through VDJ recombination and stochastic diversification of the germline antibody repertoire, however, conserved features in humoral responses to some viruses has prompted us to hypothesize that the adaptive immune system is also endowed with innate-like pattern recognition motifs that de-randomize the epitope upon which antibody responses center. This has lead to our discovery that humans possess genetically-encoded B cell receptor (BCR) sequences that naturally engage conserved sites of viral vulnerability, serving as substrates for the development of pan-neutralizing humoral responses. Interestingly, this pattern recognition depends critically on membrane surface orientation of antibody paratopes, highlighting an unexpected physical contribution to innate-like antigen recognition. We now use a combination of reconstituted BCR signaling and immunization studies to examine how this kind of pattern-recognition and B cell surface organization can be exploited to engender effective humoral responses, primarily to influenza virus and HIV.
Questions we currently exploring:
1) Can reconstituted BCR-antigen interactions predict and rank-order vaccine activity prior to use?
2) Do other conserved BCR motifs in addition to the specific germline V sequences serve as pattern-recognition motifs?
3) How does pattern-recognition shape humoral responses to vaccine targets?
4) How are vaccine antigens physically presented to the naïve BCR in vivo?