HOT TOPICS IL-17 and HIV pathogenesis Laure Campillo-Gimenez 1 , Carole Elbim 1,2 , Mireille Laforge 1 , Maria C. Leite-de-Moraes 3 , John Zaunders 4 , Jérôme Estaquier 1,5 1 Inserm, U955, Faculté de Médecine de Créteil, Créteil, France 2 Unité UMR S872, Paris, France 3 Unité UMR 8147, Faculté de Médecine René-Descartes, Paris, France 4 Centre for Immunology, St Vincent’ s Hospital, Darlinghurst, Australia 5 Assistance publique-Hôpitaux de Paris, Hôpital Henri-Mondor, Créteil, France Correspondence: J. Estaquier, Inserm U955, Faculté Créteil Henri-Mondor, 8 rue du Général Sarrail, 94010 Créteil, France <estaquier@yahoo.fr> Accepted for publication June 22, 2010 There is an increasing body of evidence showing that T H 17 cells constitute a novel T H cell lineage [1, 2]. In 2005, T H 17 cells were shown to arise from a lineage separate from that of T H 1 and T H 2 cells [1, 3], and to be associated with autoimmunity [4]. They produce IL-17 (also called CTLA-8), that shares homology with an open reading frame in Herpesvirus saimiri [5]. T H 17 cells are also characterized by the production of IL-21, IL-22 and IL-26 and express chemokine receptors such as CCR4 and CCR6 [6]. CCR6, in particular, is the homing receptor important for T H 17 cell migration to certain tis- sue microenvironments of the intestine such as Peyer’ s patches, where its ligand, CC-chemokine ligand 20 (CCL20, also known Mip-3α), is expressed [7, 8]. TGF-β, an immunosuppressive cytokine that has a major role in T reg differentiation [9], combined with the pro-inflammatory cytokine IL-6 are required for naive T cell differentiation into IL-17-producing T cells in mice [10-12]. TGF-β expression in Peyer ’ s patches has already been recognized for its role in directing B cell switching to IgA [13]. Additionally, cytokines such as IL-23 and IL-21 promote the generation or proliferation of T H 17 cells, whereas others, such as IFN-γ, IL-4, and IL-27, suppress their generation [14, 15]. The role of IL-21 in the differentiation of T H 17 is an important factor for up- regulating IL-23R expression, which is not expressed by naive cells. Thus, IL-21 promotes the expansion of T H 17 cells by increasing their responsiveness to IL-23. IL-23 is required to expand and stabilize the cell population. Although it was initially proposed that human T H 17 cells were different from mouse T H 17 cells in that TGF-β and IL-6 are not required for the generation of T H 17 cells [6, 16], other reports have shown that TGF- β and inflammatory cytokines such as IL-1β, IL-6, and IL-23 are the most effective cytokines for enhancing the generation or expansion of human T H 17 cells [17]. Among the transcription factors, it has been shown that the transcription factor retinoic-acid-related orphan receptor-γt (ROR-γt; also known as RORC) is important for the generation of T H 17 cells in vitro and in vivo [18]. In addition to ROR-γt, T H 17 cell differentiation is regu- lated by the transcription factor signal transducer and activator of transcription 3 (STAT3), and aryl hydrocar- bon receptor [19, 20]. Recently, it was shown that a dominant, negative form of STAT3, found in hyper-IgE syndrome patients, caused a primary immunodeficiency of T H 17 cells, associated with an inability to control Can- dida and S.aureus infections of skin and mucosal sur- faces [21, 22]. IL-17 comprises a family of cytokines composed of IL-17A through F [23]. Receptors belonging to the IL-17R family have a unique structural feature that mediates a signaling pathway through NF-κB activator 1 (ACT1, also known CIKS for its connection to IKK and SAPK/JNK) [24, 25], which is clearly distinct from the signatures involved in the T H 1 and T H 2 response, particularly Janus kinase (JAK)-STAT pathways. Thus, IL-17 culminates in the activation of pro-inflammatory mediators and is usually associated with innate immune signaling. Thus, IL-17 promotes neutrophil mobilization and the expression of antimicrobial factors. Interestingly, IL-17 family homologues have been found in various species including sea lamprey, rainbow trout and Caenor- habditis elegans, highlighting the potential role of this cytokine. T H 17 cells are widely found in non-lymphoid tissues (e.g. intestine) and secondary lymphoid tissues (mesen- teric lymph nodes, peripheral lymph nodes, spleen, and Peyer’ s patches). T H 17 cell differentiation in the lamina propria of the small intestine requires specific, commen- sal microbiota, and is inhibited by antibiotics. Differenti- ation of T H 17 cells correlates with the presence of Cytophaga-Flavobacterium-Bacteroides bacteria in the intestine and is dependent on TGF-β activation. Thus, it has been proposed that the composition of intestinal microbiota regulates the T H 17/Treg balance in the lamina propria, and may thus influence intestinal immunity, tol- erance, and susceptibility to inflammatory bowel diseases [26, 27]. Interestingly, Pigtail macaques (PTMs), which are highly sensitive to Simian-immunodeficiency Virus (SIV) infection, had high frequencies of interleukin- 17-producing T cells associated with high levels of 222 Eur. Cytokine Netw., Vol. 21 n° 3, September 2010, 222-5 doi: 10.1684/ecn.2010.0196