The Expression and Regulation of Amphiregulin in Human T Cells and Basophils

Abstract

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Microbiology and Immunology, 2012.Amphiregulin (AR), a member of the Epidermal Growth Factor family, is expressed during type 2 responses by activated mouse Th2 cells. AR produced by mouse hematopoietic cells contributes to the elimination of a nematode infection by a Type 2 effector response. We have now examined the regulation of expression of AR by human peripheral blood mononuclear cell T cells. Signaling through the TCR induced AR expression by human T cells, but in contrast to mouse cells, expression occurred in most or all T cell subsets, including naive and memory CD4 and CD8 T cells, Th1 and Th2 in vitro T cell lines, and subsets of memory CD4 T cells expressing several different chemokine receptors and cytokines. Strong stimuli, such as PMA and ionomycin, induced AR expression by a majority of naive and memory T cells. In addition of TCR stimulation, AR synthesis was enhanced by ligands that increased cAMP or directly activated PKA, a downstream component of the cAMP signaling pathway. Prostaglandin E2 and adenosine, natural ligands that bind to G protein coupled receptor and stimulate adenylyl cyclase activity, also enhanced AR synthesis while reducing synthesis of most other cytokines. Family of immune suppressive agents glucocorticoids, also showed opposite regulation of AR and cytokine expression. Thus AR synthesis by human T cells is regulated more by environmental signals than pre-commitment of T cells to a particular cytokine pattern. This may be appropriate for a cytokine more involved in repair than attack functions. Besides human T cells, we also observed a non-T cell population, which were basophils judged by morphology and lineage marker expression, expressing AR during human T cells activation. AR expression by basophils in response to anti-TCR stimulation required IL-3 produced by T cells, and IL-3 alone induced high levels of AR expression by purified basophils. These results suggest that the expression of AR in human immune cells also maintains a preference to type 2 immune responses through the production by basophils, which may contribute to tissue remodeling during type 2 immune responses such as asthma