Our findings allow us to construct a model of the role of T cell derived AR in adaptive immunity. During an immune response, initial immune attack mechanisms that destroy the pathogen are superseded at later times by suppression that reduces immunopathology, and tissue repair that restores normal structure and function. T lymphocytes are major cellular contributors to all three phases, and are thought to play a role in repair by producing HB-EGF and bFGF [33] . AR and HB-EGF, as members of the EGF family, promote the proliferation of fibroblasts, epithelial cells, and smooth muscle cells, which are major cell types repaired or remodeled at local tissue sites during an inflammatory response. Tissues with chronic inflammation show extensive cell proliferation, tissue thickening and reduced elasticity. Regulation of the balance between attack and repair cytokines produced by T cells is thus crucial to the successful outcome of the response. . TCR and cAMP synergize to induce AR production in human CD4 T cells. Purified CD4 T cells were incubated with or without TCR stimulation (anti-CD3/CD28 beads) and the cAMP agonist. (A) AR and HB-EGF mRNA expression was measured by RT-PCR. (B) The concentrations of AR in the supernatant and cell lysates were measured by ELISA. (C) Enriched CD45RA+CD45RO-(naïve) and CD45RA-CD45RO+ (memory) CD4 T cells were treated with medium alone, or anti-CD3/CD28 beads in the presence or absence of cAMP agonist (1 , 1000 mM) . The concentration of AR in the supernatant at 24 hours was measured by ELISA. (D) Purified CD4 T cells were treated with medium alone, or anti-CD3/CD28 beads in the presence or absence of the cAMP-modifying agents shown. RNA was extracted at 4 hours, and AR mRNA was measured by RT-PCR. The concentration of AR in the 24-hour supernatant was measured by ELISA. (E) PBMC were treated with anti-CD3+ anti-CD28 antibodies in the presence or absence of cAMP agonist or antagonist for 8 hours. CD4 T cells were purified by cell sorting and RNA was extracted. The mRNA levels of AR and other cytokines were measured by RT-PCR. All results are representative of at least three experiments. doi:10.1371/journal.pone.0039072.g007