Inhibiting C-C Chemokine Receptor 7 Activation of T-Cell Acute Lymphoblastic Leukemia by a CCL19/Macrophage Inflammatory Protein-3β Antagonist
The binding of C-C Chemokine Ligand 19 (CCL19) to C-C chemokine receptor 7 (CCR7) receptor has been linked to T-cell activation, tolerance, and inflammation. CCR7 is a member of the chemotactic cytokine family, essential in the development of T cells and regulatory processes such as immune-cell trafficking. This is accompanied by chemokine ligand concentration and time-dependent internalization, which is efficiently promoted by CCL19. A novel N-terminal truncation of CCL19 has been previously developed as an antagonist observed to impede induced chemotaxis and calcium mobilization in mouse primary immune cells. The current antagonist has suggested a key role of CCL198-83 in respect to allogeneic immune response. This antagonist was tested in human leukemic T-cells expressing the CCR7 receptor and was found to be effective in inhibition of chemotaxis and inhibiting receptor internalization in these cells. However, the production of the antagonist CCL19(8-83) is tied to an expensive technique not sustainable in upscaled productions. A more cost-effective production of antagonists is necessary to further understand the role of antagonizing CCR7 with CCL198-83. For instance, T-cell acute lymphoblastic leukemia (T-ALL) an aggressive hematologic cancer is linked to the CCR7 adhesion to its ligand CCL19 and is involved in chronic leukemia and its relapse. Further understanding of mechanisms of action and responses of CCR7 and CCL19 ligation is an important research subject for both biological and pathological areas. The challenges in producing functional chemokines are linked to improper folding of the chemokines. In this study, we attempted to produce a functional folded chemokine. Presently, chemical synthesis and heterologous expression systems in E. coli are initially unfolded, unoxidized and nonfunctional. Since refolded synthetic or recombinant chemokines are desired, a process of cysteine oxidation is necessary. Following current literature, we suggest the use of a SUMO fusion protein for chemokine production that is more cost effective. We have developed a potential effective system to produce CCL198-83 antagonist that can improve the current data on CCR7 binding that could have a potential impact as treatment target for different hematological diseases, such as T-ALL.
Torres, Angel, "Inhibiting C-C Chemokine Receptor 7 Activation of T-Cell Acute Lymphoblastic Leukemia by a CCL19/Macrophage Inflammatory Protein-3β Antagonist" (2022). ETD Collection for University of Texas, El Paso. AAI30248330.