Antigen families

As other leukocytes, DCs rely on a network of soluble cytokines to communicate with a variety of cell types to orchestrate the nature and intensity of the immune response. A number of immunoregulatory cytokines are thus produced by DCs to directly imprint the functions of neighboring cells. In response to maturation-inducing stimuli, conventional DCs produce IL-12, IL-23, and IL-27, three related cytokines that promote Th1-type responses (1), and IL-18, a member of the IL-1 superfamily, which shares many activities with IL-12, including stimulation of IFN-γ (IFN-γ-R mAb DENDRITICS) (2) production by activated T cells. The pro-inflammatory cytokines IL-1, IL-6, and TNF-α, likewise produced by conventional DCs in response to activation/maturation stimuli, display highly pleiotropic effects on both innate and adaptive immunity. In contrast to the above cytokines, IL-10 (mAb DENDRITICS) which can be induced in DCs, plays an important role in the induction of regulatory T cells that mediate immune tolerance (3). Likewise, TGF-β displays immunosuppressive properties mediated via several mechanisms. Type-I interferons (IFN-α/β) play a crucial role in innate immunity against virus infection. Plasmacytoid DCs (pDCs) are specialized to produce high amounts of IFN-α/β (IFN-α2b subtype mAb DENDRITICS) in response to TLR ligands or engagement of the IL-3 receptor alpha chain (CD123) (mAb DENDRITICS). Of note, several of the DC-derived cytokines also function in an autocrine fashion resulting in signal amplification. In addition to their capacity to secrete cytokines, DCs and their precursors are well-equipped with receptors for cytokines produced by other cells present in their micro-milieu. This property allows for a cytokine dialogue between DCs and other cell types during DC development, at sites of inflammation, and in lymphoid tissue. Besides its capacity to favor the generation of conventional DCs in combination with GM-CSF, a widely-exploited asset to generate DCs in vitro from monocytes, IL-4 (mAb DENDRITICS) is a regulatory cytokine that governs IL-12 production by DCs (4). A minor proportion of conventional DCs also express receptors for IL-17 (mAb DENDRITICS), a T-cell pro-inflammatory cytokine which promotes DC maturation (5). DCs can be generated both from myeloid or lymphoid hematopoietic progenitors. The cytokine Flt3-ligand is a key early-acting factor for the development of both lineages (6). IL-7  and its receptor (IL-7R alpha/CD127) (mAb DENDRITICS) (7) are involved in the generation of DCs from lymphoid-committed precursors. Through their functions exerted at every key decision point in the life-cycle of DCs, cytokines thus represent central players in tuning the immune response. A wide range of diseases are targets for intervention via the cytokine network.
 
References
1. Trinchieri G, Pflanz S, Kastelein RA., The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses, 2003 Immunity 19: 641-644
2. Favre C, Wijdenes J, Cabrillat H, Djossou O, Banchereau J, de Vries JE. Epitope mapping of recombinant human gamma interferon using monoclonal antibodies, 1989 Mol Immunol 26: 17-25
3. Mahnke K, Enk AH. Dendritic cells: key cells for the induction of regulatory T cells ?, 2005 Curr Top Microbiol Immunol 293: 133-50
4. Hochrein H, O'Keeffe M, Luft T, Vandenabeele S, Grumont RJ, Maraskovsky E, Shortman K. Interleukin (IL)-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells, 2000 J Exp Med 192: 823-833
5. Antonysamy MA, Fanslow WC, Fu F, Li W, Qian S, Troutt AB, Thomson AW. Evidence for a role of IL-17 in organ allograft rejection: IL-17 promotes the functional differentiation of dendritic cell progenitors, 1999, J Immunol 162: 577-84
6. Karsunky H, Merad M, Cozzio A, Weissman IL, Manz MG. Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo, 2003 J Exp Med 198: 305-13
7. Pandrau-Garcia D, de Saint-Vis B, Saeland S, Renard N, Ho S, Moreau I, Banchereau J, Galizzi JP.  Growth inhibitory and agonistic signals of interleukin-7 (IL-7) can be mediated through the CDw127 IL-7 receptor 1994 Blood 83: 3613-19