Oral Presentation The Australasian Society for Immunology 2017 Annual Scientific Meeting

TFH-derived dopamine accelerates productive T:B synapses in human germinal centres (#139)

Carola Vinuesa 1 , Ilenia Papa 1 , David Saliba 2 , Maurilio Ponzoni 3 4 , Pablo F. Canete 1 , Paula Gonzalez-Figueroa 1 , Sonia Bustamante 5 , Salvatore Valvo 2 , Rebecca Sweet 1 , Michelle Grimbaldeston 6 , Michael Meyer-Hermann 7 , Michael L. Dustin 2 , Claudio Doglioni 3 4
  1. Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
  2. Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
  3. Department of Pathology, IRCCS Scientific Institute San Raffaele, Milan, Italy
  4. University Vita-Salute San Raffaele, Milan, Italy
  5. Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW, Sydney, Australia
  6. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
  7. Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany

Protective high affinity antibody responses depend on competitive selection of B cells carrying somatically-mutated BCRs by TFH cells in germinal centres (GC). The rapid T:B synaptic interactions that occur during this process are reminiscent of those within the nervous system. Therefore, we asked whether neural transmission pathways participate in GC selection. Here we show that a proportion of human, but not mouse, GC TFH cells contained dense-core granules marked by chromogranin B, which are normally found in neuronal pre-synaptic terminals and serve to store catecholamines such as dopamine. GC TFH cells contained high concentrations of dopamine and released it upon cognate interaction with GC B cells. In a search for dopamine-mediated effects on human GC B cells, we identified selective and rapid upregulation of ICOSL. High amount of intracellular preformed ICOSL was expressed in human GC B cells and translocated to the surface within minutes of stimulation by dopamine. ICOSL was able to enhance accumulation of CD40L and chromogranin B granules at the human TFH cell synapse and increase the synapse area. Mathematical modelling suggests that faster dopamine-induced T:B interactions do not change affinity maturation but rather increase total output and accelerate it by days. Human TFH cells have co-opted yet another form of synaptic help that may provide an evolutionary advantage in the face of infection.