Aurora a shines on early t cell activation
- Autores: Noelia Blas Rus
- Directores de la Tesis: Francisco Sánchez Madrid (dir. tes.)
- Lectura: En la Universidad Autónoma de Madrid ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Manuel Fresno Escudero (presid.), Miguel Vicente Manzanares (secret.), José Ramón Regueiro González-Barros (voc.), José Luís Rodríguez Fernández (voc.), P. Roda Navarro (voc.)
- Programa de doctorado: Programa Oficial de Doctorado en Bioquímica, Biología Molecular, Biomedicina y Biotecnología (Biociencias Moleculares)
- Materias:
- Enlaces
- Tesis en acceso abierto en: Biblos-e Archivo
- Resumen
T cell activation depends on the ability of the T cell receptor (TCR) to recognize specific antigens presented in the context of the major histocompatibility complex (MHC) on the antigen-presenting cell (APC). The binding of the TCR to MHC promotes the formation of the immune synapse (IS). In this process, the TCR and its associated molecules localize to a central area of the T-cell-APC contact, the central supramolecular activating complex (cSMAC). Adhesion molecules relocate to the peripheral supramolecular activating complex (pSMAC). Essential proteins in this process are the Src family kinase members (Lck and Fyn). Lck phosphorylates the immunoreceptor tyrosine-based activation (ITAM) motifs of the TCR/CD3 complex leading to the recruitment of key molecules for the downstream signalling pathways and the IS formation. The formation of the IS also triggers changes in the tubulin cytoskeleton, including the translocation of the centrosome or microtubule (MT)-organizing centre (MTOC), to the IS, which is accompanied by the Golgi Apparatus, multivesicular bodies and mitochondria. These changes facilitate the polarized secretion of cytokines and exosomes toward the APC. MTOC polarization orchestrates active MT growth and forms the core of a dense MT network that regulates vesicular traffic at the IS.
Aurora A is a serine/threonine kinase that plays a critical role in centrosome and spindle dynamics during mitosis. During centrosome maturation, Aurora A promotes MT assembly by recruiting nucleation and stabilization factors. Due to its role in controlling MT dynamics, we hypothesized that Aurora A may play a role in the activation of T lymphocytes during IS formation. We found that Aurora A is activated upon TCR stimulation and localizes at the IS during contact. Moreover, inhibition of Aurora A with pharmacological agents or genetic deletion in human or mouse T cells severely disrupts the dynamics of microtubules and CD3-bearing vesicles at the IS. Specific targeting of Aurora A impairs activation of the TCR/CD3 complex, preventing early T cell activation and downstream expression of CD69, CD25 and IL-2. Aurora A inhibition causes delocalized clustering of Lck at the IS and decreases phosphorylation levels of tyrosine kinase Lck, thus indicating Aurora A is required for maintaining Lck active. These findings establish Aurora A as a major regulator of early signaling and the tubulin cytoskeleton during T cell activation.
