The subset of antigen-experienced CD4 T cells dedicated to skin immunology express the carbohydrate ligand for E-selectin (E-lig) along with chemokine receptor CCR4. We have developed an in vivo assay in which naive TCR-transgenic OT-II cells develop into skin-homing T cells in response to topically applied antigen. We have successfully used this assay to investigate the conditions required for naive cells to differentiate in to cutaneous memory cells, and to explore the role of CCR4 in the process by which T cells enter cutaneous tissue from the blood. Although CCR4-deficient OT-II cells are severely impaired in their ability to enter inflamed skin, they appear to replicate normally within the skin-draining lymph nodes (LN) in response to antigen. This assay employs an antigen/adjuvant combination that creates a psoriasis-like cytokine environment, generating populations of antigen-specific T cells that express IFN3 or IL17, but not common TH2-associated cytokines. CCR4-deficient T cells in this same assay did not produce IL-17, which we found to be the dominant cytokine produced by normal skin-imprinted E-lighi cells. Conversely, IFN3 expression was significantly increased for CCR4-deficient cells. To our knowledge, this is the first case in which the functional absence of a chemokine receptor has been observed to alter the TH cytokine profile of T cells responding to a given antigen. In this project, we propose to more fully explore this novel discovery, and test several hypotheses regarding the mechanism by which CCR4 ultimately influences the cytokine profile. We propose to assess expression of a wider variety of cytokines than those examined in our preliminary work to probe the full extent to which CCR4 influences this process. We will also look for differences in the expression of transcription factors associated with the various TH lineages. We will attempt to distinguish whether CCR4 influences the cytokine profile by guiding cells to a microenvironment within skin that is permissive for IL17 induction, or whether CCR4 signals directly influence TH imprinting. Furthermore, we will use various TLR ligands as adjuvants to alter the cytokine responses produced in our model, and assess the influence of CCR4 under these altered conditions. Finally, we will assess the ability of two other skin-associated chemokine receptors, CCR6 and CCR10, for their own potential to influence TH cytokine profiles in this assay.
We have made the unexpected discovery that a class of molecules called chemokine receptors can alter the cytokine response against a given antigen. Chemokine receptors are mainly known for their role in directing the migration of immune cells around the body as they engage in surveillance for unwanted invaders. We believe that our new discovery will open up an entirely new direction of research on how to positively manipulate the type of immune response in which a patient engages.
|Nizza, Suzanne T; Campbell, James J (2014) CD11b+ migratory dendritic cells mediate CD8 T cell cross-priming and cutaneous imprinting after topical immunization. PLoS One 9:e91054|
|Vander Lugt, Bryan; Tubo, Noah J; Nizza, Suzanne T et al. (2013) CCR7 plays no appreciable role in trafficking of central memory CD4 T cells to lymph nodes. J Immunol 191:3119-27|
|Rajagopal, Sudarshan; Bassoni, Daniel L; Campbell, James J et al. (2013) Biased agonism as a mechanism for differential signaling by chemokine receptors. J Biol Chem 288:35039-48|