Effector and memory T cell subsets in man and mouse
The present proposal stems from my long-standing interest in T cell differentiation and immunological memory and deals with three major questions. The first question relates to the heterogeneity of effector and memory T cells with particular regard to the recently described Th17 and Th22 subsets. We will analyze flexibility and stability of human memory Th17 and Th22 cells and attempt to further dissect the heterogeneity of effector and memory T cells using surface markers and functional assays. We will also further investigate the requirement for Th17 and Th22 cell differentiation in humans and the role these cells play in autoimmune diseases such as multiple sclerosis and psoriasis. The second question relates to the repertoire of effector and memory T cell subsets and the dynamics of human immune response. Using a recently developed analytical method to study the antigenic specificity of human T cells, we will perform a systematic analysis of frequency, distribution, and fine specificity of antigen specific T cells in naïve, effector and memory T cell subsets, in particular in the Th17 and the recently described Th22 subsets. This analysis will be performed in healthy individuals, in vaccinated donors and in patients with multiple sclerosis. The third question relates to the mechanisms that control traffic of differentiated effector and memory T cells. Here we will address the role of chemokine receptors and other homing receptors in regulating migration both of naïve, effector and memory T cells at the induction phase in antigen-stimulated lymph nodes and at the effector phase in peripheral tissues. These experiments will be conducted in the mouse system taking advantage of gene-targeted animals and models of inflammatory diseases.