Saturday, 23rd June 2018
Cell Biology and Immunology
Nitric oxide and adaptive immune response: regulation and function of nitric oxide synthase activity in the differentiation and activation of T-lymphocytes








Juan Manuel Serrador Peiró









Research summary:

Co-translocation dynamics of eNOS (green) and Golgi (red) towards the immune synapse of a T cell stimulated with superantigen-pulsed-APC (blue). Each frame shows DIC pictures superimposed on the fluorescence images. Time from initial cell contact is indicated in minutes at the lower left corner.
T cells expressing eNOS-GFP (green) were transiently co-transfected with the Ras binding domain of Raf-1 (YFP-RBD) and CFP-N-Ras. The sequence shows the redistribution of RBD (yellow) towards N-Ras (cyan) as a marker of N-Ras activation on the Golgi complex of a T cell stimulated with an antigen-pulsed APC (blue). 

The scientific major interest of our group is focused on the study of nitric oxide (NO) and the regulation of the adaptive immune responses associated with the degenerative damage in autoimmune-related diseases with major public health impact, chiefly underlying the cellular and molecular basis of these pathological processes but also applying a health perspective. We are particularly interested in the study of the role played by NO on the differentiation and activation of T lymphocytes and its consequences on the course of autoimmunity. There are evidences indicating a role for endothelial nitric oxide synthase (eNOS) in the genesis and exacerbation of chronic inflammation.

More recently, we have also demonstrated that T lymphocytes express eNOS and that eNOS-derived NO regulates antigen-dependent T lymphocyte activation at the immune synapse. Moreover, we have found that eNOS activity is mainly localized on the Golgi complex where positively regulates Ras/ERK activation in T cells stimulated with antigen on antigen-presenting cells (APCs). The regulation of the Ras/ERK signalling pathway in antigen-stimulated T cells is based on the eNOS-dependent specific activation of N-Ras but not K-Ras on the Golgi complex and involves S-nitrosylation of N-Ras on Cys118. Currently, the scientific priority of our studies is to explore whether eNOS-derived NO from antigen-stimulated T lymphocytes plays a major role in Th1, Th2, and/or Th17 cell differentiation, and whether this role may take place during the adaptive inflammatory processes underlying the damage of tissues in inflammatory autoimmune diseases.


Relevant publications:

Nitrosothiols in the immune system: signaling and protection.

Hernansanz-Agustín P, Izquierdo-Álvarez A, García-Ortiz A, Ibiza S, Serrador JM, Martínez-Ruiz A.

Antioxid Redox Signal. 2013 Jan 20;18(3):288-308. doi: 10.1089/ars.2012.4765. Epub 2012 Aug 17.

PMID:  22746191

The mitochondrial fission factor dynamin-related protein 1 modulates T-cell receptor signalling at the immune synapse.

Baixauli F, Martín-Cófreces NB, Morlino G, Carrasco YR, Calabia-Linares C, Veiga E, Serrador JM, Sánchez-Madrid F.

EMBO J. 2011 Apr 6;30(7):1238-50. doi: 10.1038/emboj.2011.25. Epub 2011 Feb 15.

PMID:  21326213

Bringing up the rear: defining the roles of the uropod.

Sánchez-Madrid F, Serrador JM.

Nat Rev Mol Cell Biol. 2009 May;10(5):353-9. doi: 10.1038/nrm2680. Epub 2009 Apr 17.

PMID:  19373240

Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells.

Ibiza S, Pérez-Rodríguez A, Ortega A, Martínez-Ruiz A, Barreiro O, García-Domínguez CA, Víctor VM, Esplugues JV, Rojas JM, Sánchez-Madrid F, Serrador JM.

Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10507-12. doi: 10.1073/pnas.0711062105. Epub 2008 Jul 18.

PMID:  18641128

Endothelial nitric oxide synthase regulates T cell receptor signaling at the immunological synapse.

Ibiza S, Víctor VM, Boscá I, Ortega A, Urzainqui A, O'Connor JE, Sánchez-Madrid F, Esplugues JV, Serrador JM.

Immunity. 2006 Jun;24(6):753-65.

PMID:  16782031