Jesús M Salvador Lab Centro Nacional de Biotecnología (CNB)

T cell activation and differentiation in tumor suppression and autoimmunity

Research

Research Interest

  • Regulation of T cell activation and differentiation in autoimmunity, inflammation and cancer
  • Generation of murine models to study the role of the Gadd45 family and p38 MAPK signaling in tumor suppression and autoimmunity
  • Screenings to identify new therapeutic targets in inflammation, autoimmune diseases and cancer
  • Validation of the therapeutic targets in human patients

The main goal of our group is the study of the molecular mechanisms that regulate lymphocyte activation and differentiation: a) to understand why and how dysregulation of any of theses processes lead to development of human inflammatory disorders, autoimmune diseases or cancer and b) to identify novel therapeutic targets in the treatment of these diseases.

To address this goal we are focus on the function of the Gadd45 (growth arrest and DNA damage-inducible gene) family and the p38 MAPK (mitogen-activated protein kinase) in lymphocyte activation, differentiation, apoptosis and cytokine production.

Our recent findings on the role of the autoimmune suppressor Gadd45a and p38 MAPK signaling challenged current dogmas on immune cell regulation and demonstrated a new T cell signaling pathway important in autoimmune disease development. We identified a novel regulatory site (Tyr323) in p38, whose phosphorylation activates p38 in the absence of the upstream MAPKK pathway components. These findings established a specific new target (Tyr323) for experimental therapeutics in autoimmune diseases.

There are currently several p38 inhibitors in clinical trials as anti-inflammatory and immunosuppressor drugs. Because of p38’s central role in the production of pro-inflammatory cytokines (TNFα, IL-1 and IL-6), it has attracted a great deal of attention as a potential drug target. Our results suggest that selective inhibition of the alternative p38 activation pathway is a very attractive pharmacological target, due to its T cell specificity. Identification of positive or negative regulators (such as Gadd45 family proteins) of this pathway will be critical for understanding the molecular mechanisms involved in development of autoimmune disease and cancer.

We are dissecting the signaling pathways involved in development of autoimmunity and cancer using a multidisciplinary approach that combines mouse genetic, human epigenetic, biochemical, molecular biological and immunological techniques. Currently, we are developing and characterizing murine models of autoimmune disease and cancer, analyzing the in vivo and in vitro function of Gadd45 and p38 MAPK in T cell activation, proliferation, apoptosis and differentiation, and validating these results in autoimmune disease and cancer patients.

Autoinmune glomerolunephritis in Gadd45a-/- and Gadd45a/p21-/- mice