Transcriptional basis of lymphocyte tolerance Madhuri Borde Robert A. Barrington Vigo Heissmeyer Michael C. Carroll Anjana Rao Authors’ addresses Madhuri Borde 1 , Robert A. Barrington 1 , Vigo Heissmeyer 1 *, Michael C. Carroll 1,2 , Anjana Rao 1 1 The CBR Institute for Biomedical Research and the Department of Pathology, Harvard Medical School, Boston, MA, USA. 2 Department of Pediatrics, Children’s Hospital, Boston, MA, USA. *Present address: National Research Center for Environment and Health-GSF, Institute of Molecular Immunology, Munich, Germany. Correspondence to: Anjana Rao The CBR Institute for Biomedical Research Warren Alpert Building, Harvard Medical School 200 Longwood Avenue Boston, MA 02115 USA Tel.: +1 617 278 3260 Fax: +1 617 278 3280 E-mail: arao@cbr.med.harvard.edu Summary: Signaling through lymphocyte antigen receptors has the potential to initiate several distinct outcomes: proliferation, differentia- tion, apoptosis, or functional unresponsiveness. Expansion and differen- tiation of effector T cells is required for defense against foreign antigens, whereas functional unresponsiveness, termed anergy, is a cell-intrinsic mechanism that contributes to peripheral self-tolerance. Other mechan- isms of peripheral tolerance include the ‘dominant’ tolerance imposed by regulatory T cells and immunosuppression mediated by interleukin-10 and transforming growth factor-b. T- and B-cell antigen receptor ligation induces an increase in intracellular calcium levels as well as activating additional signaling pathways that are further potentiated by costimula- tory receptors. In this review, we argue that cell-intrinsic programs of peripheral anergy and tolerance are imposed by sustained calcium signal- ing in lymphocytes. We address in particular the role of the calcium- dependent transcription factor nuclear factor for activation of T cells, which is activated by antigen receptor stimulation and, depending on the presence or absence of input from its transcriptional partner, activator protein-1, dictates two distinct transcriptional programs: activation or tolerance. Introduction Lymphocytes must maintain a delicate balance between recog- nition and clearance of foreign pathogens on the one hand and tolerance to self on the other. The antigen receptors of T and B cells are randomly generated through somatic recombi- nation. While this process allows for a diverse repertoire of antigen-specific lymphocytes, it can also lead to the produc- tion of T and B cells that are autoreactive. As a consequence, several mechanisms have evolved to protect against T and B cells harboring the potential to recognize and become acti- vated by self-antigens. Central tolerance takes place during T-cell development in the thymus to prevent the maturation of autoreactive T cells (1–4). Most self-reactive T cells are deleted in a process termed negative selection, but certain CD4 + T cells are deviated to the CD25 + regulatory T-cell lineage (5–7). The fact that circulating autoreactive T cells Immunological Reviews 2006 Vol. 210: 105–119 Printed in Singapore. All rights reserved ß 2006 The Authors Journal compilation ß 2006 Blackwell Munksgaard Immunological Reviews 0105-2896 105