Highways, byways and breadcrumbs: directing lymphocyte traffic in the lymph node Marc Baje ´ noff 1, 2* , Jackson G. Egen 1* , Hai Qi 1 , Alex Y.C. Huang 3 , Flora Castellino 4 and Ronald N. Germain 1 1 Lymphocyte Biology Section, Laboratory of Immunology, NIAID, NIH, Bethesda, MD 20892, USA 2 INSERM U344, Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, Universite ´ de Nice-Sophia-Antipolis, Valbonne, France 3 Division of Pediatric Hematology/Oncology, Rainbow Babies & Children’s Hospital, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA 4 Novartis Vaccines, Via Fiorentina 1, Siena 53100, Italy The lymph node (LN) is charged with a crucial function in the mammalian immune system: to facilitate physical interactions between extremely rare cells arriving from different tissue compartments. Paramount to carrying out this function is its unique placement at the interface between the blood and lymphatic systems, thus enabling tissue-derived antigen and antigen-presenting cells, especially dendritic cells (DCs) to gather in close proximity to blood-derived antigen-specific motile lymphocytes. A generally held view is that this accumulation of cells, coupled with stochastic migration, is itself sufficient to facilitate a physiologically adequate frequency of cell–cell contacts due to random migration within the confined space of the LN. Based on recent data, we propose an expanded model of LN function in which unique archi- tectural features and chemical signals together provide a means of enhancing otherwise unlikely encounters be- tween sparse DCs and rare antigen-specific lymphocytes. Finding the needle in the haystack Lymphocytes specific for a particular antigen are rare in the naive repertoire. In the case of naive T lymphocytes, the number of cells reactive to a given peptide–MHC complex ranges from 1 in 10 5 to 1 in 10 6 [1,6]. Thus, a fundamental challenge faced by the adaptive immune system is how to use an extremely small population of antigen-specific naive lymphocytes to detect and respond efficiently to the pres- ence of a pathogen in any of countless locations throughout the entire body. The lymphatic drainage system provides one solution to this problem by concentrating tissue-derived interstitial fluids (lymph) in one or more regional lymph nodes (LNs). Lymph derived from a defined volume of tissue will contain antigens and antigen-presenting cells repre- senting the immunogenic contents of that particular site. Consequently, to survey for a potential infection with pathogen, the naı ¨ve lymphocyte simply needs to patrol all LNs in search of cognate antigen without having to wander through every tissue and organ [2,3]. Although the ability of a lymphocyte to visit all LNs is crucial for surveying widely for potential infections, it can also be thought of as distracting the cell from where it is needed the most following infection, i.e. the LN draining the infected site. Considering the spleen together with the 22 different LNs in the mouse [4] or the 450 LNs in the human, not to mention other sites of organized lymphoid tissue, such as Peyer’s patches, it becomes evident that finding the relevant LN that has a few ’interesting’ den- dritic cells (DCs) is a significant challenge for rare antigen- specific T cells. Upon entering the relevant LN, the antigen-specific T cell must then locate DCs bearing cognate antigen in the midst of millions of unspecific lymphoid and myeloid cells. The volume of a resting LN is roughly 10 million times the volume of a naı¨ve T cell and this potential search space will further expand with LN remodeling during inflammation. Thus, at precisely the time when the T cell needs to find its antigen-loaded DCs, it must migrate through an environ- ment that is increasing its size and complexity, markedly amplifying the difficulty of the task. If the time taken to find the right partner cell was not important, these issues of cell number and search space would not be relevant. However, when dealing with an infectious pathogen, time is, in fact, a key parameter. For example, most bacteria have a very fast doubling rate (20 min for E. coli) and, as a consequence, a few hours difference in controlling the spread and/or the replication of a pathogen could be the difference between life and death for the host. In this respect, any mechanism that can decrease the search time becomes crucial. This concept applies especially during the initial stages of an infection, when the quantities of antigen are limited, requiring the T cell to ‘excel’ in its hunt for rare antigen-loaded DCs. All together, these combined elements lead to the simple question: What strategies might the immune system uti- lize to facilitate the ability of antigen-specific lymphocytes to find a relevant LN and rapidly identify antigen-bearing Opinion TRENDS in Immunology Vol.28 No.8 Corresponding author: Germain, R.N. (rgermain@niaid.nih.gov). * These authors contributed equally to this work. Available online 10 July 2007. www.sciencedirect.com 1471-4906/$ – see front matter . Published by Elsevier Ltd. doi:10.1016/j.it.2007.06.005