Back to the thymus: peripheral T cells come home

Abstract

The thymus has long been known as the generative organ for the T-cell arm of the immune system. To perform this role, the thymus was thought to require protection from antigenic and cellular insult from the 'outside world', with the notable exception of the continual influx of progenitor cells required to initiate the complicated process of T-cell differentiation. Overwhelming evidence that mature T cells can recirculate and persist in the thymus has required us to revamp this earlier view of the thymus as detached from outside influence. In this review, we consider the evidence for T-cell recirculation into the thymus, discuss the likely means and location of mature T-cell entry, and speculate on the potential consequences of such close apposition between differentiating thymocytes and mature recirculating lymphocytes.

Figure 1. T cell development proceeds through the checkpoints of β selection, positive selection, and negative selection as developing thymocytes migrate through distinct thymic microenvironments. Reentering mature T cells may intersect this pathway, possibly impacting both positive and negative selection

(a) and (i) Progenitor cells and mature peripheral T cells both likely enter the thymus through post-capillary venules at the cortico-medullary junction. Developing thymocytes (depicted as light blue cells) follow the migration patterns detailed below, while reentering mature peripheral T cells (depicted as dark blue cells) persist mainly, although not exclusively, in the medulla. (b) Developing T cells migrate to the outer cortex of the thymus and recombine TCRβ chain genes. Successful generation of a TCRβ chain drives cells to (c) proliferate and (d) co-express CD4 and CD8 coreceptors, and migrate deeper into the cortex. (e) DP thymocytes rearrange TCRα gene segments. Surface expression of the resulting TCRαβ molecules is required for positive selection, driven most efficiently by low-affinity interaction with self-MHC complexes on cortical thymic epithelial cells (cTECS). Positively selected cells will commit to the appropriate CD8 or CD4 T cell lineage. (f) The resulting SP thymocytes migrate into the medulla. In the medulla (g), expression of tissue-specific antigens by medullary thymic epithelial cells (mTECs) and presentation of self-antigens by dendritic cells (DC) enforce central tolerance by the clonal deletion of self-reactive SP thymocytes. (h) Mature CD4SP and CD8SP thymocytes likely exit via the post-capillary venules at the cortico-medullary junction.

Figure 2. Mature peripheral T cells recirculate to the thymus of unmanipulated mice

Thymocytes from RAG2p-GFP mice were analyzed by flow cytometry for cell surface markers and GFP. (a) Representative dot plots from an approximately 70 week old mouse, showing that populations gated as CD4SP (left) and CD8SP (right) contain GFP⁺ SP thymocytes and GFP⁻ mature T cells that have reentered the thymus. (b) Cells gated as CD4SP (left) and CD8SP (right) were counterstained with the indicated antibodies to reveal the cell surface phenotype of GFP⁻ (open histograms) and GFP⁺ cells (filled histograms). The GFP⁻ populations consist of predominantly mature (CD24^lowQa2^hi) and previously activated (CD44^hi) cells. (c) The percent of the total SP thymic compartment comprised of reentering peripheral T cells increases with age. (d) The number of GFP⁻ mature T cells found in the thymus initially increases and then remains relatively stable with age.