interleukin-21; effector/memory CD8 T cells; regulatory T cells; Th1/Th2/Th17; inflammatory bowel disease; asthma; IL-21; Treg; Th subsets; inflammation
Attridge K, Wang CH, Wardzinski L, Kenefeck R, Chamberlain JL, Manzotti C, Kopf M, Walker LS (2012), IL-21 inhibits T cell IL-2 production and impairs Treg homeostasi, in Blood
, 119(20), 4656-4664.
Attridge Kesley, Wang Chun Jing, Wardzinski Lukasz, Kenefeck Rupert, Chamberlain Jayne L, Manzotti Claire, Kopf Manfred, Walker Lucy S K (2012), IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis., in Blood
, 119(20), 4656-64.
Kisielow Jan, Tortola Luigi, Weber Jacqueline, Karjalainen Klaus, Kopf Manfred (2011), Evidence for the divergence of innate and adaptive T-cell precursors before commitment to the αβ and γδ lineages., in Blood
, 118(25), 6591-600.
Kopf Manfred, Bachmann Martin F, Marsland Benjamin J (2010), Averting inflammation by targeting the cytokine environment., in Nature reviews. Drug discovery
, 9(9), 703-18.
Bessa Juliana, Kopf Manfred, Bachmann Martin F (2010), Cutting edge: IL-21 and TLR signaling regulate germinal center responses in a B cell-intrinsic manner., in Journal of immunology (Baltimore, Md. : 1950)
, 184(9), 4615-9.
Songhet Pascal, Barthel Manja, Röhn Till A, Van Maele Laurye, Cayet Delphine, Sirard Jean-Claude, Bachmann Martin, Kopf Manfred, Hardt Wolf-Dietrich (2010), IL-17A/F-signaling does not contribute to the initial phase of mucosal inflammation triggered by S. Typhimurium., in PloS one
, 5(11), 13804-13804.
Tortola Luigi, Yadava Koshika, Bachmann Martin F, Müller Christoph, Kisielow Jan, Kopf Manfred (2010), IL-21 induces death of marginal zone B cells during chronic inflammation., in Blood
, 116(24), 5200-7.
Kopf Manfred (2009), IL-17–producing T cells in lung immunity and inflammation, in J Allergy Clin Immunol
, 123(5), 986-994.
Fröhlich Anja, Kisielow Jan, Schmitz Iwana, Freigang Stefan, Shamshiev Abdijapar T, Weber Jacqueline, Marsland Benjamin J, Oxenius Annette, Kopf Manfred (2009), IL-21R on T cells is critical for sustained functionality and control of chronic viral infection., in Science (New York, N.Y.)
, 324(5934), 1576-80.
CD4+ T helper (Th) cells orchestrate immune responses by differentiating into discrete subsets characterized by distinct cytokine secretion patterns. Th2 cells shape effector responses during allergy and Helminth infections by secretion of a panel of cytokines including IL-4, IL-5, IL-10, and IL-13. Th1 cells mediate control of bacterial, protozoan, and fungal infection by production of IFN-?. Recently a novel subset termed Th17 cells have been shown to mediate organ related auto-immune diseases by production of IL-17. Another population of CD4 T cells with regulatory function (Treg) keeps these CD4 effector T cell subsets in check by secretion of the anti-inflammatory cytokines such IL-10 and TGF-ß, or by other yet undefined mechanisms. Cytokines determine not only effector function of T cells subsets but also their fate by inducing lineage specific transcription factors in naïve precursor CD4 T cells. IL-21 is the most recently described member of the type I cytokine family including IL-2, IL-4, IL-7, IL-9, and IL-15; their receptors share the common ?c chain and signal via the Jak/STAT pathway. These cytokines play crucial roles in T cell responses including cell proliferation, differentiation, and maintaining memory populations, besides their activity on many other cell types of the immune system. Specifically, IL-4 is critical for Th2 cell differentiation and effector responses. IL-7 is required for T cell development and, together with IL-15, in maintenance of memory CD8 T cells. IL-2 is central for tolerance induction by promoting maintenance and function of Treg. Moreover, it is critical for expansion of memory cells following secondary rather than primary infection. IL-21 has been shown to promote differentiation and/or responses of Th1, Th2, and Th17 cells dependent on the experimental system, but the results remain relatively controversial. In addition, IL-21 has also been suggested to promote CD8 T cell responses and to inhibit differentiation of inducible regulatory T cells (Treg). However, its role in control of anti-viral CD8 T cell responses and homeostasis and function of regulatory T cells in vivo remains poorly described. We have generated IL-21R-/- mice and initiated studies to 1: Define the role of IL-21/IL-21R in acute and chronic viral infection2: Characterize function of regulatory T cells in IL-21R-/- miceSpecifically, under aim 2, we intend to investigate:2.1: The role of IL-21 in the balance of regulatory T cells and Th2 cells in asthma2.2: The status of regulatory T cells and control of leishmaniasis in the context of IL-21.2.3: The roles of IL-21 vs IL-2 in intestinal homeostasis and inflammation.These studies should provide important data to further understand basic mechanisms of T cell differentiation, effector and memory responses with direct implications for research and therapy of important diseases such as asthma, colitis, and viral infection.