Our Science – Singer Website

Alfred Singer, M.D.

Experimental Immunology Branch Head, Lymphocyte Development Section Branch Chief Building 10, Room 4B36 10 Center Drive Bethesda, MD 20892 Phone:   301-496-5461 Fax:   301-496-0887 E-Mail:   singera@nih.gov

Biography

Dr. Singer received his M.D. from Columbia University and his clinical training at the Columbia-Presbyterian Medical Center. He was a fellow in immunology at the Rockefeller University before coming to the NCI. He is chief of the Experimental Immunology Branch and his research interests are in lymphocyte recognition and development, especially the molecular and cellular recognition signals that result in self/nonself discrimination during early development.

Research

Lymphocyte Development

Development of all T cells takes place in the thymus and proceeds via an ordered sequence of developmental steps that is best described by changing expression patterns of surface CD4/CD8 coreceptor molecules. Each differentiation step is signaled by components of the T cell antigen receptor (TCR) complex. The differentiation of immature CD4+8+ (double positive, DP) thymocytes into mature T cells is the key event in T cell development as it gives rise to functional T cells and determines the mature T cell repertoire. DP thymocytes expressing TCR with appropriate specificities are “positively selected� to further differentiate into mature T cells, while DP thymocytes expressing potentially autoreactive TCR are “negatively selected� and removed. The end result is a mature T cell repertoire that is reactive against foreign antigens but tolerant of self components. It is one of the paradoxes of thymic selection that both positive and negative selection is based on TCR specificity for intrathymic MHC/peptide complexes. Adding to the complexity of thymic selection is that TCR specificity additionally determines lineage direction, with TCR-signaled DP thymocytes differentiating into either CD4+ T helper cells or CD8+ T cytotoxic cells. Elucidating the cellular interactions and molecular signals that regulate these intrathymic events has been the major focus of our research program.

One of our major recent efforts has focused on identifying the molecular mechanisms by which a developing DP thymocyte determines its appropriate cell fate. In this regard we have developed an experimental in vitro model of positive selection that led us to a number of startling observations and discoveries that flatly contradicted accepted paradigms. We have discovered that DP thymocytes initially terminate CD8 gene transcription, even when differentiating into mature CD8+ T cells, so that signaled DP thymocytes transcriptionally become CD4+8- intermediate cells regardless of their TCR specificity. It is at this CD4+8- intermediate stage of differentiation that the decision to become either a CD4+ helper or CD8+ cytolytic cell is made. The decision to become a CD8+ T cell requires IL-7 that permits thymocytes to extinguish CD4 gene transcription and reinitiate CD8 transcription, novel molecular events we have referred to as “coreceptor reversal.� We have synthesized our experimental results into a new model of thymocyte differentiation and lineage determination called kinetic signaling that applies not only to DP thymocytes, but also to bipotential cells in multiple biological systems.

This page was last updated on 9/9/2005.