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T-Cell Development


Acknowledgment

The authors wish to thank Marcia McDuffie, MD, Anthony R. Hayward, MD, PhD, and Luigi Notarangelo, MD, PhD, who contributed exceptionally to previous editions of this chapter in the third edition of Fetal and Neonatal Physiology .

Introduction

Hematopoietic stem cells give rise to committed progenitors of multiple lineages. Whereas maturation along myeloid, erythroid, and megakaryocytic cell lineages occurs within the bone marrow, and differentiation into B lymphocytes initiates in the bone marrow and is completed in the periphery, T-lymphocyte development occurs within the thymus, where bone marrow–derived common lymphoid progenitors migrate. In particular, interaction of lymphoid progenitors with thymic stromal cells permits differentiation of CD4 − and CD8 − , double-negative cells into CD4 + and CD8 + , double-positive (DP) thymocytes within the thymus cortex. Subsequently, DP cells lose expression of either CD4 or CD8, becoming functionally active single-positive cells that populate the thymic medulla ( Fig. 116.1 ).

Fig. 116.1, T-cell development and selection in the thymus. Hematopoietic stem cells (HSCs) with self-renewing capacity give rise to pluripotent progenitor cells (PPCs) that may differentiate to common myeloid progenitors (CMPs) or common lymphoid progenitors (CLPs) . CLPs, in turn, differentiate into T-cell-restricted precursors (indicated in green ), in addition to giving rise to natural killer (NK) cells, plasmacytoid dendritic cells (pDCs) , and B cells. T-cell lineage-restricted cells then pass through pre-T1, pre-T2, early double-positive (DP) , DP, and single-positive (SP) stages in the thymic cortex and medulla. T cells at the pre-T1 differentiation stage express CD1a and initiate T-cell receptor (TCR) rearrangement. Next, they express CD4 but not CD8 and are referred to as CD4 + immature cells. Further maturation gives rise to cells expressing both CD4 and CD8 markers, in addition to TCR/CD3 . These cells are subjected to positive selection in the thymic cortex. DP thymocytes then differentiate into CD4 + or CD8 + SP cells. After post-selection maturation in the medulla, T cells are exported to the periphery.

Although the thymus is particularly active early in life, it ensures lifelong generation of a pool of newly generated T cells. Of importance, the thymus also plays a critical role in purging self-reactive T lymphocytes. Therefore T cells produced in the thymus carry a seemingly unrestricted antigen receptor repertoire, whose reactivity is largely restricted to foreign antigens and is tolerant to self-antigens.

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