Evolution of thymopoietic microenvironments

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.

Keywords: Foxn1; adaptive immunity; antigen receptor; self-tolerance; thymus; vertebrate.

Figure 1.

Evolution of thymopoiesis. This scheme synthesizes information relevant to the emergence of the thymus as a primary lymphoid organ in vertebrates. The character states in cephalochordates, tunicates and the vertebrate ancestor are hypothetical and are inferred from reconstruction experiments discussed in the text. With respect to thymus morphology, note that it is unclear whether the pharynx of cephalochordates and tunicates exhibits a lymphopoietic tissue (dotted lines for thymus morphology and thymopoietic properties); the orange area indicates the cortex, light blue the medulla. The symbol L refers to a hypothetical primordial lymphocyte lineage before the establishment of distinct T and B lineages. For extant vertebrates, the lineage-specific thymopoietic properties are indicated by the different sizes of circles. Quality control refers to the process of selection for self-compatibility imposed on the primary repertoire of somatically diversified antigen receptors.