The development of T cell-mediated autoimmune and inflammatory disorders, as well as allograft rejection, depends in part on the homing of pathogenic T cells to the target site. Although the basic molecular mechanisms by which leukocytes are recruited to specific target tissues are clear, there are significant gaps in our knowledge regarding how these processes are controlled in T cells. Selectins are a family of carbohydrate-binding adhesion molecules well established to play a crucial role in leukocyte traffic. Activated T cells, particularly T helper 1 (Th1) cells, are known to express ligands for E-selectin and P-selectin, two members of the selectin gene family which are expressed on endothelium, and expression of these carbohydrate ligands is essential for recruitment of these inflammatory Th1 cells to sites of inflammation. We have shown that IL- 12 is important for the induction of certain glycosyltransferases (GT) that are crucial for the formation of selectin ligands in Th1 cells. Among these GT are the alpha1, 3 fucosyltransferase FucT-VII and the 0-glycan branching enzyme core 2 beta1, 6 glucosaminyltransferase 1 (C2G1cNAcT-I). However, the precise role of different GT in the biosynthesis of distinct ligands for different selectins is not clear, nor is it known how the expression of these enzymes is controlled. We have uncovered evidence for multiple pathways which control the expression of different GT in Th1 cells in response to different stimuli. Unraveling how these various pathways control the expression of the multiple relevant GT involved in selectin ligand biosynthesis in CD4 cells is the overall theme of this proposal. In the first aim, we will continue to identify GT which play a role in selectin ligand biosynthesis in developing Th1 cells and determine if they are part of a Th1 homing program. In the second aim, we will explore the relationship between selectin ligand expression and T cell memory. In the third aim, we will explore the role of MAP kinases in controlling selectin ligand formation in Th1 cells. In the fourth aim, we will begin to uncover the genetic basis for how expression of FucT-VII is controlled in Th1 cells. Collectively, these studies will determine how inflammatory T cell migration is controlled, and uncover new targets and pathways for amelioration of T cell-mediated autoimmune and inflammatory disorders.
| Mathur, Anubhav N; Chang, Hua-Chen; Zisoulis, Dimitrios G et al. (2007) Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 178:4901-7 |
