About 500 million years ago, a new type of adaptive immune defense emerged in basal jawed vertebrates, accompanied by morphological innovations, including the thymus. Did these evolutionary novelties arise de novo or from elaboration of ancient genetic networks? We reconstructed the genetic changes underlying thymopoiesis by comparative genome and expression analyses in chordates and basal vertebrates. The derived models of genetic networks were experimentally verified in bony fishes. Ancestral networks defining circumscribed regions of the pharyngeal epithelium of jawless vertebrates expanded in cartilaginous fishes to incorporate novel genes, notably those encoding chemokines. Correspondingly, novel networks evolved in lymphocytes of jawed vertebrates to control the expression of additional chemokine receptors. These complementary changes enabled unprecedented Delta/Notch signaling between pharyngeal epithelium and lymphoid cells that was exploited for specification to the T cell lineage. Our results provide a framework elucidating the evolution of key features of the adaptive immune system in jawed vertebrates.
We report in this work the expression and characterization of class I molecules expressed as single-chain trimers consisting of an antigenic peptide-spacer-β2-microglobulin-spacer H chain. Our results indicate that these single-chain constructs assemble efficiently, maintain their covalent structure, and are unusually stable at the cell surface. Consequently, these constructs are at least 1000-fold less accessible to exogenous peptide than class I molecules loaded with endogenous peptides, and they are potent simulators of peptide-specific CTL and Abs. Our combined findings suggest that single-chain trimers may have applications as DNA vaccines against virus infection or tumors.
The transcription factor c-myb has emerged as one of the key regulators of vertebrate hematopoiesis. In mice, it is dispensable for primitive stages of blood cell development but essentially required for definitive hematopoiesis. Using a conditional knock-out strategy, recent studies have indicated that c-myb is required for self-renewal of mouse hematopoietic stem cells. Here, we describe and characterize the c-myb mutant in a lower vertebrate, the zebrafish Danio rerio . The recessive loss-of-function allele of c-myb ( c-myb t25127 ) was identified in a collection of N -ethyl- N -nitrosourea (ENU)-induced mutants exhibiting a failure of thymopoiesis. The sequence of the mutant allele predicts a missense mutation (I181N) in the middle of the DNA recognition helix of repeat 3 of the highly conserved DNA binding domain. In keeping with the findings in the mouse, primitive hematopoiesis is not affected in the c-myb mutant fish. By contrast, definitive hematopoiesis fails, resulting in the loss of all blood cells by day 20 of development. Thus, the mutant fish lack lymphocytes and other white and red blood cells; nonetheless, they survive for 2–3 mo but show stunted growth. Because the mutant fish survive into early adulthood, it was possible to directly show that their definitive hematopoiesis is permanently extinguished. Our results, therefore, suggest that the key role of c-myb in definitive hematopoiesis is similar to that in mammals and must have become established early in vertebrate evolution.
The thymus is a lymphoid organ unique to vertebrates, and it provides a unique microenvironment that facilitates the differentiation of immature hematopoietic precursors into mature T cells. We subjected the evolutionary trajectory of the thymic microenvironment to experimental analysis. A hypothetical primordial form of the thymus was established in mice by replacing FOXN1, the vertebrate-specific master regulator of thymic epithelial cell function, with its metazoan ancestor, FOXN4, thereby resetting the regulatory and coding changes that have occurred since the divergence of these two paralogs. FOXN4 exhibited substantial thymopoietic activity. Unexpectedly, histological changes and a functional imbalance between the lymphopoietic cytokine IL7 and the T cell specification factor DLL4 within the reconstructed thymus resulted in coincident but spatially segregated T and B cell development. Our results identify an evolutionary mechanism underlying the conversion of a general lymphopoietic organ to a site of exclusive T cell generation.
By analyzing T cell responses against foreign major histocompatibility complex (MHC) molecules loaded with peptide libraries and defined self- and viral peptides, we demonstrate a profound influence of self-MHC molecules on the repertoire of alloreactive T cells: the closer the foreign MHC molecule is related to the T cell's MHC, the higher is the proportion of peptide-specific, alloreactive (“allorestricted”) T cells versus T cells recognizing the foreign MHC molecule without regard to the peptide in the groove. Thus, the peptide repertoire of alloreactive T cells must be influenced by self-MHC molecules during positive or negative thymic selection or peripheral survival, much like the repertoire of the self-restricted T cells. In consequence, allorestricted, peptide-specific T cells (that are of interest for clinical applications) are easier to obtain if T cells and target cells express related MHC molecules.
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