TFH-derived dopamine accelerates productive synapses in germinal centres

• Published in: Nature (London) 2017-07, Vol.547 (7663), p.318-323
• Main Authors: Papa, Ilenia, Saliba, David, Ponzoni, Maurilio, Bustamante, Sonia, Canete, Pablo F., Gonzalez-Figueroa, Paula, McNamara, Hayley A., Valvo, Salvatore, Grimbaldeston, Michele, Sweet, Rebecca A., Vohra, Harpreet, Cockburn, Ian A., Meyer-Hermann, Michael, Dustin, Michael L., Doglioni, Claudio, Vinuesa, Carola G.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/51; 14; 14/28; 14/34; 14/63; 14/69; 38; 38/77; 631/250; 631/250/2152/2153/1982; Dopamine; Humanities and Social Sciences; multidisciplinary; Physiological aspects; Science; Synapses; T cells
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature23013

Protective high-affinity antibody responses depend on competitive selection of B cells carrying somatically mutated B-cell receptors by follicular helper T (T FH ) cells in germinal centres. The rapid T–B-cell interactions that occur during this process are reminiscent of neural synaptic transmission pathways. Here we show that a proportion of human T FH cells contain dense-core granules marked by chromogranin B, which are normally found in neuronal presynaptic terminals storing catecholamines such as dopamine. T FH cells produce high amounts of dopamine and release it upon cognate interaction with B cells. Dopamine causes rapid translocation of intracellular ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) to the B-cell surface, which enhances accumulation of CD40L and chromogranin B granules at the human T FH cell synapse and increases the synapse area. Mathematical modelling suggests that faster dopamine-induced T–B-cell interactions increase total germinal centre output and accelerate it by days. Delivery of neurotransmitters across the T–B-cell synapse may be advantageous in the face of infection. Human follicular helper T cells engaging in synaptic interactions with germinal centre B cells release dopamine stored in chromogranin B + granules, causing rapid externalization of ICOS ligand, which in turn enhances CD40L delivery to the synaptic cleft and synaptic contact, and results in an accelerated response. Dopamine accelerates immune response Carola Vinuesa and colleagues study the mechanisms that govern the maturation of the high-affinity B cells in germinal centres. They identify a subset of follicular helper T cells that carry dopamine-containing dense-core granules normally found in neuronal pre-synaptic terminals, and show that dopamine can act on human B cells, inducing the expression of ICOS ligand on the B cell surface. This enhances CD40L clustering and synaptic contact, resulting in an accelerated response. A faster response could be advantageous in cases of infections by rapidly evolving viruses.