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Contenido archivado el 2024-05-29

Regulation of immune responses and autoimmunity by activating and inhibitory NK receptors expressed by T lymphocytes: role of ITAM versus ITIM signal balance

Objetivo

Immune cell activity is regulated by both activating and inhibitory receptors, which transduce signals through two motifs: ITAM and ITIM, respectively. ITIM receptors play a key role in the regulation of ITAM induced activation of leukocytes, thus creating a balance, which regulates cellular functions and the outcome of the immune response (immune priming or tolerance).

Moreover aberrant expression of activating and/or inhibitory immune receptors and of their ligands can lead to deleterious effects, including autoimmunity. While inhibitory NK receptors are also often expressed by normal T cells, the activating counterparts are mostly found on pathogenic self reactive T cells in autoimmune diseases.

Transgenic mice expressing activating receptor Ly49D/DAP12 an d/or its inhibitory counterpart Ly49A (in presence/absence of H 2Dd as ligand) offer the opportunity to better understand the role of ITAM/ITIM balance in T cell biology, and the relevance of T cell ITAM signalling (via DAP12) in autoimmunity.

We first pro pose to address T lymphocyte differentiation in Ly49D/DAP12 transgenic mice, by studying thymocyte development and TCR repertoire selection. Peripheral T lymphocyte function will be investigated upon Ly49D engagement alone or in combination with TCR stimulation.

With the aim to assess the function of activating receptors expressed by CD8+ T cells in autoimmunity, a model of diabetes will be used (RIP-LCMV mice). The CD8+ T cells of the Ly49D/DAP12 transgenic mice will be will be transferred into RIP LCMV G P transgenic mice, whose beta islet cells express LCMV GP (lymphocytic choriomeningitis glycoprotein) as self antigen.

In this model, self-reactive CD8+ T cells trigger diabetes only upon adequate stimulation (e.g. LMCV infection, CD28/B7.2 costimulation). We will test whether ITAM signalling via Ly49D/DAP12 is sufficient to trigger diabetes. Consequently this approach might allow bringing new insight in autoimmunity to design novel appropriate treatments.

Ámbito científico (EuroSciVoc)

Palabras clave

Tema(s)

Convocatoria de propuestas

FP6-2004-MOBILITY-5
Consulte otros proyectos de esta convocatoria

Régimen de financiación

EIF - Marie Curie actions-Intra-European Fellowships

Coordinador

LUDWIG INSTITUTE FOR CANCER RESEARCH, LAUSANNE BRANCH
Aportación de la UE
Sin datos
Coste total
Sin datos