Max D. Cooper, MD
Pathology & Laboratory Medicine
Emory University School of Medicine
Dental Building, Fourth Floor
1462 Clifton Road
Atlanta, GA 30322, USA
Professor, Pathology & Laboratory Medicine
Georgia Research Alliance Eminent Scholar in Developmental Immunology
Member, The Emory Vaccine Center
Adaptive Immune System DevelopmentOriginally defined in comparative analysis of immune system development in birds and mammals, T and B lymphocytes serve as the primary antigen recognition and effector cells of specific adaptive immunity. T cells provide specific immunity against viruses, fungi, and other intracellular pathogens, and they help B cells produce antibodies against extracellular pathogens and toxins. The T cells are generated from precursor cells within the thymus of all jawed vertebrates. Immunoglobulin (Ig)-bearing B cells are generated from precursor cells within the bursa of Fabricius in birds and in the blood-forming tissues of other jawed vertebrates, primarily the fetal liver and adult bone marrow in mammals. In these central lymphoid tissues, the progeny of hematopoietic stem cells are influenced by neighboring stromal cells to initiate elaborate gene programs and undergo proliferation to generate millions of T and B cell clones, each of which expresses a T cell receptor (TCR) or a B cell receptor (BCR) of different antigen specificity. Before migrating from the thymus or bone marrow through the bloodstream to the periphery, newly formed T and B cells are positively or negatively selected on the basis of receptor-binding affinity for self-antigens. In peripheral lymphoid tissues, such as the spleen, intestine, and lymph nodes, they collaborate with antigen-presenting cells and each other to undergo antigen-driven clonal proliferation and differentiation to provide protective immediate immunity and subsequent memory of the antigen encounter. Inherited or acquired gene defects can alter T and B cell development to cause life-threatening immunodeficiencies, autoimmunity, or lymphoid malignancies.
Fc Receptor-like Molecules on B cellsUsing a consensus sequence derived from the Ig Fc-binding sites of classical Fc receptors, our group along with two other groups of investigators identified a family of genes that encode Fc receptor-like molecules (FCRLs). The six FCRL genes are located near the classical FcR genes on human chromosome 1q21. They encode cell surface molecules with 3 to 9 Ig-like extracellular domains, a transmembrane region, and cytoplasmic domains containing consensus immunoreceptor tyrosine-based activating and/or inhibitory motifs. These features suggested that the FCRLs have immunomodulatory potential. The first five FCRLs are expressed at different stages in B cell differentiation. One of them, FCRL1, is expressed at highest levels on naive B cells, where it may serve as an activating coreceptor. Conversely, FCRL4 has potent inhibitory potential and is expressed on a tissue-based subpopulation of memory B cells, where it may inhibit BCR-mediated proliferation to favor plasma cell differentiation and antibody production. The intrigue of the FCRL family is heightened by their highly conserved nature, close relatives having been identified in fish, frogs, birds and other mammals. Our ongoing studies seek to define FCRL ligands, signaling pathways, normal function in antibody responses, and potential dysfunction in B cell malignancies and autoimmune diseases.
Phylogenetic Origin of Specific Adaptive ImmunitySince the recognition of separate T and B cell lineages, a long-standing question has been which cell type came first. Although all multicellular organisms possess innate immune defense mechanisms, only the jawed vertebrates have been found to have T, B, and antigen-presenting cells. The requisite genes for BCR, TCR, and the major histocompatability complex (MHC) have not been found in invertebrates or even in jawless vertebrates. In a search for insight into the origin of adaptive immunity in jawless vertebrates, we analyzed transcripts expressed by lymphocyte-like cells in the lamprey, one of two surviving jawless vertebrates. This analysis identified genes used for innate immune responses and others that may control lamprey lymphocyte development, intracellular signaling, proliferation, and migration. Lamprey gene relatives of mammalian genes involved in antigen processing and transport of antigenic peptides were found, but MHC-like genes were not.
Our studies led to the surprising discovery that two very different types of adaptive immune systems have evolved in vertebrates. The surviving jawless vertebrates, lamprey and hagfish, have a lymphocyte antigen receptor repertoire that we found to be potentially as large as that of the antibody repertoire (>1014) in mice and humans. However, unlike our Ig-based T cell receptors and B cell receptors for antigens, the agnathan variable lymphocyte receptors (VLR) are composed of multiple leucine rich repeats (LRR) and an invariant stalk region tethered via glycosyl-phosphatidyl-inositol anchorage to the lymphocyte surface. The diverse VLR [put in italics] genes are generated somatically by a gene conversion mechanism for a multistep, piecewise assembly process in which flanking LRR sequences are stitched into an incomplete germline VLR [put in italics] gene. VLR diversity is based upon differences in sequences and numbers of the constituent LRR modules. Monoallelic assembly and expression of unique VLR [put in italics] genes by individual cells results in the generation of a clonally diverse lymphocyte population, members of which can be selected for specific immune responses. We have found that immunized lamprey undergo antigen induced lymphocyte activation, proliferation and differentiation to produce multivalent VLR antibodies with precise binding specificity for protein and carbohydrate antigenic determinants on bacteria, viruses, and mammalian blood cells. The secreted lamprey antibodies are composed of eight or ten identical subunits held together at their base by disulfide bonds. Remarkable antigen specificity, avidity, stability and ease of molecular engineering suggest many potential biomedical uses for monoclonal VLR antibodies. Our current studies explore some of these possibilities.