Available online at www.sciencedirect.com Cytokine crosstalk for thymic medulla formation Takeshi Nitta, Izumi Ohigashi, Yasushi Nakagawa and Yousuke Takahama The medullary microenvironment of the thymus plays a crucial role in the establishment of self-tolerance through the deletion of self-reactive thymocytes and the generation of regulatory T cells. Crosstalk or bidirectional signal exchanges between developing thymocytes and medullary thymic epithelial cells (mTECs) contribute to the formation of the thymic medulla. Recent studies have identified the molecules that mediate thymic crosstalk. Tumor necrosis factor superfamily cytokines, including RANKL, CD40L, and lymphotoxin, produced by positively selected thymocytes and lymphoid tissue inducer cells promote the proliferation and differentiation of mTECs. In return, CCR7 ligand chemokines produced by mTECs facilitate the migration of positively selected thymocytes to the medulla. The cytokine crosstalk between developing thymocytes and mTECs nurtures the formation of the thymic medulla and thereby regulates the establishment of self-tolerance. Address Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan Corresponding author: Takahama, Yousuke (takahama@genome.tokushima-u.ac.jp) Current Opinion in Immunology 2011, 23:190–197 This review comes from a themed issue on Lymphocyte development Edited by Kristin Hogquist and Eugene Oltz Available online 30th December 2010 0952-7915/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2010.12.002 Introduction The parenchyma of the thymus comprises two major microenvironments of the cortex and the medulla. The cortex–medulla structure of the thymus is shared among vertebrate species carrying the thymus, from fish to human [1]. The cortex is the microenvironment for early T-lymphopoiesis as well as for the positive and negative selection of newly generated CD4 + CD8 + (double- positive, DP) thymocytes that express cell-surface T cell antigen receptors (TCRs) in low amounts. On the con- trary, the thymic medulla serves to trim the repertoire of positively selected thymocytes in order to aid the estab- lishment of self-tolerance [2–4]. The boundary region between the cortex and the medulla, called the cortico- medullary junction, is rich in vasculature and serves as the intersection for cell trafficking between the thymic par- enchyma and the extrathymic circulation [5,6]. The thymic medulla consists of various cell types of hematopoietic and nonhematopoietic cell lineages. Hematopoietic cells in the thymic medulla include CD4 + CD8  and CD4  CD8 + single-positive (SP) thymo- cytes expressing cell-surface TCRs in medium to high amounts. The majority of SP thymocytes are newly generated T cells that have been positively selected in the thymic cortex and transported to the medulla. These SP thymocytes are estimated to spend four to five days in the thymic medulla before being exported to the circula- tion [7]. In addition to these newly generated T cells, medullary SP thymocytes contain mature T cells that are recirculated from the periphery [8–10]. Other hemato- poietic cells enriched in the thymic medulla include dendritic cells (DCs) [11]. Thymic DCs are either gener- ated in the thymus from lymphopoietic progenitor cells [12] or derived from the circulation [13]. Whether the different origin of thymic DCs is linked to the different localization in the thymus is unclear, but a recent report shows that blood-borne thymic DCs are detected in the thymic cortex [14]. Other hematopoietic cells, including macrophages, B cells, and natural killer cells, are also found in the thymic medulla [15]. Nonhematopoietic cells in the thymic medulla include medullary thymic epithelial cells (mTECs), mesenchy- mal cells, and endothelial cells. mTECs are hetero- geneous as regards morphology and molecular expression profiles [15,16]. A fraction of mTECs form concentric and reticular structures called Hassall’s cor- puscles [15,17]. In the peripheral region of the thymic medulla, or around the cortico-medullary junction, endo- thelial vessels are surrounded by mesenchymal cells to form a perivascular space between those two cell types. The perivascular space is thought to be the route between the thymic parenchyma and the circulation for hemato- poietic cells, including T-lymphopoietic progenitor cells immigrating into the thymus and newly generated T lymphocytes exported to the circulation [18,19]. Lym- phatic vessels as well as myoid cells and nerve cells are also present in the thymic medulla [5,15,20]. The major function of the thymic medulla is the contri- bution to the establishment of self-tolerance, by trimming the repertoire of newly generated SP thymocytes that have been positively selected in the thymic cortex. In many cases of mouse models and human diseases where the thymic medulla is defective, T cell development per se is not arrested but self-tolerance governed by T cells is broken down and signs of autoimmunity arise. For example, in mice deficient for the transcription factor RelB, the formation of the thymic medulla is markedly Current Opinion in Immunology 2011, 23:190–197 www.sciencedirect.com