The role Of T Cell activation in type 1 diabetes; T cell differentiation versus T cell tolerance

Obiettivo

The proposal presented here represents a continuation of the work I have done in the USA on

T lymphocyte peripheral tolerance and autoimmune diabetes. My goal is to gain a better

understanding of the disregulation of the mechanisms of immune tolerance leading to the activation of

autoreactive T cells in autoimmune processes. This will allow us to rationally design new therapeutic

strategies against type 1 diabetes in particular that can prevent or stop the progression of the disease

before insulin function is lost. These forms of therapy are inexistent at the present time.

The interplay among three types of cells plays an important role in the onset of type 1 diabetes.

These are CD8+ T cells, CD4+ T helper cells and antigen presenting cells (APCs). In a normal

situation, tolerogenic APCs will pick and transport self-antigens from the parenchyma to the draining

lymph nodes where they will silence CD8+ and CD4+ T cells. If CD4+ T cell tolerance fails, CD4+

helper cells will activate APCs that in turn will promote the differentiation of potentially autoreactive

CD8+ T cells into diabetogenic killer cells. Based on this hypothesis, the aim of this project is to

decipher the cellular and molecular interactions responsible for the establishment of T cell tolerance to

pancreatic antigens and the activation of potentially autoreactive T cells leading to autoimmunity.

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