Ronald N. Germain, M.D., Ph.D.

Deputy Chief, Laboratory of Immunology
Chief, Lymphocyte Biology Section

Description of Research Program

The Lymphocyte Biology Section (LBS) studies basic aspects of how white blood cells called T lymphocytes recognize foreign substances known as antigens. The work of the laboratory is organized around three themes within this larger topic: 1) the formation of peptide complexes with major histocompatibility complex (MHC) molecules, which are the ligands for the antigen-specific receptors (TCR) of αß T cells; 2) the role of recognition of self-peptide:MHC molecule ligands in the development of T cells in the thymus gland; and 3) the biochemical mechanisms involved in allowing TCR to discriminate between self and foreign peptide-associated MHC molecules, including the control of T-cell differentiation by the TCR signals generated by these recognition events.

Antigen Processing and Presentation

Among the early contributions of LBS to the field of antigen processing and presentation are

• Proposing that MHC class I and class II molecules capture antigenic peptides in different intracellular locations
• Providing the first accurate model of the structure of an MHC molecule peptide-binding domain
• Describing the transport-promoting properties of the invariant chain and the role of the CLIP region of invariant chain in controlling class II folding and transport
• Discovering the role of peptide in controlling the biochemical and biological stability of class II dimers
• Describing the complex trafficking of class II and the invariant chain through multiple endocytic organelles prior to surface expression

Recent work in this area includes the identification of a novel transport signal within class II molecules themselves and the first direct evidence that antigen presentation by MHC class II molecules involves binding to large protein fragments and not peptides, followed by cleavage of the bound protein to peptide length. This latter finding provides new insight into why the MHC class II molecule evolved a binding site with open ends—namely, to accommodate the large proteins that are its preferred substrates. LBS has also pioneered the development of reagents (monoclonal antibodies) that can detect specific peptide-MHC molecule complexes, and the use of these tools for the in vivo visualization of antigen presentation to T cells. This work has led to a new understanding of which cells actually process and present antigen, the kinetics of presentation, and the role of inflammatory signals in effective dendritic cell antigen processing and colocalization with T cells for the initiation of adaptive immune responses.

A second major focus of the LBS is on the consequences of T-cell receptor recognition of peptide-MHC molecule complexes, especially how binding events are translated into intracellular signals that regulate T-cell differentiation. Among the major previous accomplishments of LBS in this area are the identification of the site(s) of CD4:MHC class II interaction, description of TCR antagonists and partial agonists, and discovery that such ligands induce a distinct set of early intracellular tyrosine phosphorylation events.

Ongoing work centers on understanding the differences in intracellular signals generated by agonist versus partial agonists/antagonists, examining the molecular interactions that account for normal and altered signaling, and exploring the biological consequences of altered signaling in immunity. Very exciting data are now emerging from these studies, which have revealed previously unsuspected feedback regulatory pathways that help the T cell achieve fine discrimination between ligands of closely related structure. Such selectivity is at the heart of physiologic self/nonself-discrimination by the immune system. These experiments also have clarified the role of negative regulatory molecules, such as SHP-1, in the phenomenon of TCR antagonism and in regulating the strength and duration of TCR signaling by activating ligands.

Finally, we have continued to study the development of T cells in the thymus. Our work in this area has led to a new and increasingly accepted model of the stages of thymocyte differentiation. We have now developed a new model system for examining the role of antigen-specific and -unspecific signals in T-cell lineage (CD4 versus CD8) choice, as well as the nature of TCR signaling leading to effective positive and negative selection. This work is closely dovetailed with the biochemical studies on TCR signaling and recently has led to the novel finding that the TCR changes its perception of ligand during maturation in a highly selective manner that supports self/nonself discrimination in the periphery. These biochemical and developmental studies are being integrated with modern methods for global gene expression analysis to reveal the changes that accompany and control each step of maturation.

Memberships

• Sigma Xi
• American Association of Immunologists

Advisory/Review Boards

• Ruggero Ceppellini Advanced School of Immunology (Naples, Italy)
• Roche Milano Ricerche
• Howard Hughes Medical Institute

Editorial Boards

• The Journal of Experimental Medicine
• Immunity
• Scandinavian Journal of Immunology
• Current Biology
• Annual Review of Immunology

Selected Publications

(View list in PubMed.)

Germain RN, Miller MJ, Dustin ML, Nussenzweig MC. Dynamic imaging of the immune system: progress, pitfalls and promise. Nat Rev Immunol. 2006 Jul;6(7):497-507. 

Qi H, Egen JG, Huang AY, Germain RN. Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science. 2006 Jun 16;312(5780):1672-6. 

Benoist C, Germain RN, Mathis D. A plaidoyer for 'systems immunology'. Immunol Rev. 2006 Apr;210:229-34. 

Castellino F, Huang AY, Altan-Bonnet G, Stoll S, Scheinecker C, Germain RN. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature. 2006 Apr 13;440(7086):890-5. 

Castellino F, Germain RN. Cooperation between CD4+ and CD8+ T cells: when, where, and how. Annu Rev Immunol. 2006;24:519-40. 

Bajenoff M, Breart B, Huang AY, Qi H, Cazareth J, Braud VM, Germain RN, Glaichenhaus N. Natural killer cell behavior in lymph nodes revealed by static and real-time imaging. J Exp Med. 2006 Mar 20;203(3):619-31.  

Special Interest Groups
Immunology, Cell Biology, Protein Trafficking

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