No significant difference in the clinical scores was found in the mice transferred with WT or CCR6/Treg cells (data not shown). Th17 ELF3 cell migration. The CD4+Th cells are central organizers in immune responses. Naive T cells, upon activation by APCs, differentiate into cytokine-expressing effector Th cells, which have been historically classified into Th1 and Th2 lineages based on their cytokine secretion and immune regulatory function (1,2). Th1 cells regulate cellular immunity and Ag presentation through secreting IFN-, while Th2 cells mediate the humoral and allergic responses by producing Clindamycin palmitate HCl IL-4, IL-5, and IL-13. Th1 and Th2 cells differ not only in their immune function but also in their migratory regulation; they express distinct chemokine receptors which mediate their selective recruitments into tissues depending on the types of pathogen infections or immune responses (3). In addition to Th1 and Th2, a third subset of Th cells, namely, Th17, was recently identified (46). Th17 cells were first marked by IL-17 production and subsequently were found to also secret IL-17F and IL-22 (5,79). IL-17 has been previously found to be involved in host defenses against bacterial infection (10). Recently, Th17 cells have been strongly associated in autoimmune diseases, such as animal models for multiple sclerosis and rheumatoid arthritis (5,6,11,12). Neutralizing IL-17 strongly inhibited experimental autoimmune encephalomyelitis (EAE)3(5,6). Th17 differentiation is potently driven by TGF-and IL-6 (1315), which is reinforced by IL-23 (16,17). Recently, IL-21 was reported as an autocrine factor induced by IL-6 to regulate Th17 differentiation (1719). For cytokine-mediated Th17 differentiation, STAT3 was found to be a necessary transcription factor (16,20). STAT3 may function by regulating the expression of lineage-specific master transcription factor(s), such as RORt and ROR, two orphan nuclear receptors that were recently shown to regulate Th17 differentiation (21,22). In contrast to autoimmunity-promoting Th17 cells, thymus-derived natural regulatory T cells (nTreg) represent a unique subpopulation of CD4+T cells that inhibits T cell proliferation and autoimmune responses (23). The hallmark of nTreg cells is the expression of Foxp3 transcription factor, which serves as a master regulator of Treg cell development and function (24). Under the influence of TGF-, Foxp3 can be also induced in naive T cells’ periphery and the resulting inducible Treg (iTreg) cells exhibit the same suppressive phenotype as nTreg (24). Interestingly, both iTreg and Th17 cell development depends on TGF-. Thus, there is not only functional antagonism between Th17 cells and Treg cells in autoimmunity, but also a reciprocal regulation in the generation of these cells. Although TGF-induces Foxp3 expression, IL-6 and IL-21 inhibit this regulation and along with TGF-drive Th17 differentiation. Despite recent progress on understanding the regulation and function of Treg and Th17 cells, it is unclear how their recruitments into inflammatory sites are regulated. In this study, we report that both Treg and Th17 cells express CCR6. Th17 cells also express the CCR6 ligand CCL20, through which Th17 promotes the migration of Th17 and Treg cells. CCR6 deficiency in T cells decreases the susceptibility to autoimmune diseases. Lack of CCR6 in Th17 cells inhibits their own as well as Treg recruitment into inflammatory tissues. Clindamycin palmitate HCl Similarly, CCR6 on Treg cells is also important for Clindamycin palmitate HCl their Clindamycin palmitate HCl recruitment into inflammatory tissues. Our data thus Clindamycin palmitate HCl indicate an essential role of CCR6 in Treg and Th17 migration in autoimmune disease and suggest that Th17 induces both amplification and inhibition mechanisms on inflammatory responses via CCR6. == Materials and Methods == == Mice == C57BL/6 mice, CCR6 knockout (KO), Rag1 KO, B6.SJL-PtprcaPepcb/BoyJ (CD45.1) mice were purchased from The Jackson Laboratory. RORKO, ROR/double mutant mice, STAT3 conditional KO, and IL-21 KO mice have been previously described (16,19,22). All animal experiments have been conducted under the animal protocols approved by M.D. Anderson Cancer Center Institutional Animal Care and Usage Committee. == T cell differentiation == CD4+CD25CD62LhighCD44lowcells were isolated by FACS sorting as described before (16,19). Naive CD4+T cells.