Abstract
In vertebrates, the development of lymphocytes from undifferentiated haematopoietic precursors takes place in so-called primary lymphoid organs, such as the thymus. Therein, lymphocytes undergo a complex differentiation and selection process that culminates in the generation of a pool of mature T cells that collectively express a self-tolerant repertoire of somatically diversified antigen receptors. Throughout this entire process, the microenvironment of the thymus in large parts dictates the sequence and outcome of the lymphopoietic activity. In vertebrates, direct genetic evidence in some species and circumstantial evidence in others suggest that the formation of a functional thymic microenvironment is controlled by members of the Foxn1/4 family of transcription factors. In teleost fishes, both Foxn1 and Foxn4 contribute to thymopoietic activity, whereas Foxn1 is both necessary and sufficient in the mammalian thymus. The evolutionary history of Foxn1/4 genes suggests that an ancient Foxn4 gene lineage gave rise to the Foxn1 genes in early vertebrates, raising the question of the thymopoietic capacity of the ancestor common to all vertebrates. Recent attempts to reconstruct the early events in the evolution of thymopoietic tissues by replacement of the mouse Foxn1 gene by Foxn1-like genes isolated from various chordate species suggest a plausible scenario. It appears that the primordial thymus was a bi-potent lymphoid organ, supporting both B cell and T cell development; however, during the course of vertebrate, evolution B cell development was gradually diminished converting the thymus into a site specialized in T cell development.
Highlights
Adaptive immune systems of vertebrates rely on the formation and expression of randomly generated antigen receptor repertoires in their lymphocyte lineages
It appears that the primordial thymus was a bi-potent lymphoid organ, supporting both B cell and T cell development; during the course of vertebrate, evolution B cell development was gradually diminished converting the thymus into a site specialized in T cell development
The apparent discrepancy of antigen receptor structures and assembly mechanisms leaves unanswered the question of whether or not the common ancestor of vertebrates already possessed a system for somatic diversification: did it consist of one of the two extant forms, or perhaps even an alternative— extinct—system? Be this as it may, the vast diversity of somatically generated antigen receptors underlying the adaptive immune systems of vertebrates raises the question as to how the repertoire can be purged of self-destructive reactivities—and ignore self—yet retain the capacity to recognize non-self or altered self-structures
Summary
Adaptive immune systems of vertebrates rely on the formation and expression of randomly generated antigen receptor repertoires in their lymphocyte lineages. The evolutionary solution to this problem has been the emergence of specialized lymphoid organs, wherein differentiation of lymphocytes, the formation of functional antigen receptors, and the subsequent quality control of the emerging receptor repertoire are spatially coupled [10] These coordinated activities are the raison dêtre of so-called primary lymphoid organs such as the thymus. We touch upon the general structure of the thymic microenvironment in order to highlight its role in supporting the development of T cells and the associated quality control of the TCR repertoire for selfcompatibility This summary sets the stage for a discussion of the evolutionary history of a transcription factor family whose diversification appears to be directly coupled to the changes in the lymphopoietic activity of the thymus during the approximately 500 million years of vertebrate evolution
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