T cell fate specification and alphabeta/gammadelta lineage commitment

The development of T cells from pluripotent stem cells involves a coordinated series of lineage-commitment steps. Common lymphoid precursors in the fetal liver or adult bone marrow must first choose between a T, B or NK cell fate. Committed T cell precursors in the thymus then differentiate into cells committed to the alphabeta or gammadelta lineages. Recent advances have been made in our understanding of the mechanisms underlying T cell fate specification and alphabeta/gammadelta lineage divergence.     

Transcription factor regulation of B lineage commitment

The past year has provided insight into the mechanisms by which multipotent progenitors commit to differentiation through the B lymphocyte lineage. Mice lacking the Pax5 gene develop pro-B lymphocytes but these cells are not uniquely committed to the B lineage as they can give rise to all hematopoietic cell types if cultured under appropriate conditions. Regulators of lymphocyte proliferation and survival have also been identified that may allow lymphocytes to respond to information provided by the external environment.     

Selection and lineage specification in the thymus: commitment 4-stalled

How CD4(+)CD8(+) thymocytes commit to CD4 helper versus CD8 cytotoxic lineages is a central unresolved question in developmental immunology. In this issue, show that engineering CD4 for shutoff immediately after positive selection misdirects cells to the cytotoxic lineage. The result highlights the distinction between positive selection and lineage commitment and provides new impetus for reexamining lineage models.     

Molecular and cellular basis of T cell lineage commitment

The thymus forms as an alymphoid thymic primordium with T cell differentiation requiring the seeding of this anlage. This review will focus on the characteristics of the hematopoietic progenitors which colonize the thymus and their subsequent commitment/differentiation, both in mice and men. Within the thymus, the interplay between Notch1 and IL-7 signals is crucial for the orchestration of T cell development, but the precise requirements for these factors in murine and human thympoeisis are not synonymous. Recent advances in our understanding of the mechanisms regulating precursor entry and their maintenance in the thymus will also be presented.     

Transcriptional regulation of mast cell and basophil lineage commitment

Basophils and mast cells have long been known to play critical roles in allergic disease and in immunity against parasitic infection. Accumulated evidence also supports that basophils and mast cells have important roles in immune regulations, host defense against bacteria and viruses, and autoimmune diseases. However, origin and molecular regulation of basophil and mast cell differentiation remain incompletely understood. In this review, we focus on recent advances in the understanding of origin and molecular regulation of mouse and human basophil and mast cell development. A more complete understanding of how basophils and mast cells develop at the molecular level will lead to development of interventions that are more effective in achieving long-term success.     

Regulatory T cell lineage commitment in the thymus

A substantial fraction of the Foxp3⁺ CD4⁺ regulatory T (T_reg) cell repertoire is generated through instructive and/or selective processes in the thymus, and there is some consensus that clonal deviation into the T_reg lineage is a result of self-antigen recognition. Paradoxically, the same holds true for a diametrically different cell fate decision of developing thymocytes, namely their removal from the repertoire through apoptotic cell death (clonal deletion). Here, we will review our current understanding of how T cell receptor stimulation, cytokine signaling, co-stimulation, epigenetic modifications and T cell intrinsic developmental tuning synergize during T_reg cell differentiation, and how instructive signals converge at the Foxp3 gene-locus during entry into the T_reg cell lineage. We will also discuss how these parameters relate to known determinants of negative selection.     

B cell commitment.

Multipotential stem cells have the capacity to differentiate into a variety of cell types including B lymphocytes. The development of B cells from multipotential progenitors has been the subject of numerous studies and many aspects of this transition are well characterized. However, the initial genetic events which commit a stem cell to follow the B lineage developmental pathway have not yet been discovered. In this review we examine diverse experiments which may lead to increased understanding of the important first steps in the commitment process.     

Progenitor migration to the thymus and T cell lineage commitment

T cells developing in the thymus are ultimately derived from bone marrow (BM) hematopoietic stem cells (HSCs). An understanding of the developmental steps between HSCs and T cells is important for gaining insight into cancers of the T lineage, improving T cell reconstitution after BM transplantation, and also to help ameliorate immunological defects in aging. In this article, we summarize our current understanding of the inter-related fields of early T cell development and thymic aging, and briefly discuss major unresolved questions in this field.