seminars in CANCER BIOLOGY, Vol. 12, 2002: pp. 301–308 doi:10.1016/S1044–579X(02)00016-0, available online at http://www.idealibrary.com on Dendritic cells, antigen distribution and the initiation of primary immune responses to self and non-self antigens Stella C. Knight * , Fiona Burke and Penelope A. Bedford Immunity or tolerance are determined through the bone marrow-derived, antigen-presenting cells, dendritic cells (DC). Stimulation of lymphocytes by different types of DC, DC at different stages of maturity and DC producing and responding to different growth factors modulate immune responses. Innate receptors for foreign or self antigens provide scope in DC for discrimination between different antigenic stimuli. DC also transfer processed antigens to other DC. We propose that DC do not stimulate responses to antigens in their own environment but only to antigens acquired from other DC, providing a mechanism for discriminating between environmental and non-environmental antigens. Key words: tolerance induction / primary immune respon- ses / innate receptors on dendritic cells / auto-immunity / tumour immunity Crown Copyright © 2002 Published by Elsevier Science Ltd. All rights reserved. Introduction The central immunological question of the basis for self/non-self discrimination lies at the heart of un- derstanding and manipulating tumour immunity. Cell-mediated immunity and the development of cy- totoxic T lymphocytes (CTL) can mediate rejection of tumours. This adaptive arm of the immune response is dependent for its elicitation on the presentation of antigen by primary antigen presenting cells, dendritic cells (DC). 1 DC are the only known potent stimulator cells for primary adaptive immune responses in T and B cells directed at either self or non-self antigens. 2,3 Na¨ ıve T lymphocytes are not generally located within From the Antigen Presentation Research Group, Northwick Park Institute for Medical Research, Imperial College Faculty of Medicine, Watford Rd., Harrow HA1 3UJ, UK. *Corresponding author. E-mail: s.knight@ic.ac.uk Crown Copyright © 2002 Published by Elsevier Science Ltd. All rights reserved. 1044–579X / 02 / $ – see front matter peripheral tissues but localise within specialised lym- phoid organs. DC acquire antigens in the periphery, carry them to the draining lymph nodes and cause the aggregation and stimulation of na¨ ıve lymphocytes. 4 The introduction of antigen to the lymphocytes by intermediary DC means that two fundamental aspects of this adaptive immune response may be determined through these DC—whether or not there is an adap- tive immune response and, secondly, the nature of that response. Possession of fine specificity for the targets of adap- tive immune responses within lymphocyte popula- tions evolved through the use of specific receptor molecules such as the T cell receptor and antibody molecules of B cells. DC, despite lacking these spe- cific receptor molecules, discriminate between types of antigens encountered. Antigen-capture by imma- ture DC in the periphery results in the local pro- duction of chemokines and cytokines, which may amplify the innate immune response and promote maturation of DC. 5 Antigenic exposure can also pro- mote migration of DC from the peripheral tissues into lymphoid tissue and their development from antigen-processing cells to antigen-presenting cells. 6 Whole viruses or bacteria or their proteins or pep- tides can produce a spectrum of different responses in DC; DC can be biased towards production of those cytokines believed to polarise T cells towards the T helper (Th)-1 or Th-2 type of response. 7 The maturation process and the different cytokine pro- files induced by various antigens provide evidence of antigenic discrimination by DC and is revealing a plethora of innate mechanisms present within the immature DC that may influence their behaviour and function. In this article, some of the innate capacities of DC to respond to antigenic exposure, the interface be- tween these factors and the development of adaptive immune response in lymphocytes will be considered. Special emphasis will be made on the importance of antigen distribution on DC populations. Our own studies are providing evidence that the exquisite 301