Thymocyte Trafficking

6.1. Entry into the thymus and trafficking to the subcapsule

The process by which undifferentiated lymphocyte precursors progress into fully mature self-tolerant T lymphocytes requires several changes in receptor expression and involves detailed movements through regions of the thymus [101-104]. A layer of connective tissue called the thymic capsule surrounds the thymus and extends into septa that divide the thymus into separate lobules. Lining the connective tissue is a layer of subcapsular epithelium that acts as a barrier to control cell movement to and from the thymus. A subset of haematopoietic progenitor cells having escaped from bone marrow, enter the thymus cortex from vessels within the septa and migrate to the subcapsular region. The exact entry point into the thymus has yet to be characterized. The earliest cells immigrating into the thymus have been localized to areas within the vasculature of the cortex, cortical-medullary junction (CMJ), and medulla [105]. Since an impermeable endothelial layer surrounds blood vessels in the cortex, some propose that progenitor cells enter the thymus into the medullary region and traverse "upstream" to the outer cortex/subcapsule [103]. Cells entering the subcapsular region are CD4 CD8" double-negative (DN) progenitor cells. During their maturation, progenitor cells commit fully to the T lymphocyte lineage, where rearrangement of their TCR genes is supported by thymic stromal cell expression of IL-7 and c-kit [106,107], The abundant expression of thymic CXCL12 /SDF-1 suggested CXCR4 as a candidate for thymocyte entry; however, several lines of evidence indicate the contrary: treatment of CD34+ T cell precursors with anti-CXCR4 antibodies had no effect on the colonization of fetal thymic organ cultures [108], and CXCR4 is not expressed on CD34+ progenitor cells within peripheral blood [95], Although CXCR4 is not expressed on DN early immigrant cells, it is later upregulated during their maturation to CD4+CD8+ double-positive (DP) cells [101,109],

6.2. Transition from double-negative to double-positive cells

There are four distinct stages of maturation between DN cells and CD4+CD8+ DP cells. These stages are marked by the expression of the CD44 and CD25 cell surface molecules. Through these stages, cells progress from an early CD44+CD25 phenotype to CD44+CD25+, CD44 CD25+, and finally back to a CD44 CD25 profile. Upregulation of CD4 and CD8 expression coincides with the final acquisition of the CD44 CD25 profile [103], CXCR4 has been implicated in regulating the progression of cells to the DP state. Murine CD44+CD25 early DN cells have been reported to migrate weakly in response to CXCL12/SDF-1, with the response increasing as the cells progress to CD44CD25 [110]. Similarly, Suzuki et al. [25] reported that CD44+CD25 cells have low expression of CXCR4 that is upregulated upon progression to the more mature CD44+CD25+ phenotype but downregulated in CD4 or CD8 single-positive (SP) cells.

The chemokine receptor CCR9 and its ligand CCL25/thymus-expressed chemokine (TECK) have also been implicated in T lymphocyte development. CCL25/TECK induces migration in day 14 fetal thymocytes [111] and bone marrow cells from CCR9' mice were less efficient than wild-type animals at repopulating the thy mi of irradiated Rag-1mice [112]. While DN cells are CCR9", CCR9 expression is induced in the transition to DP cells and is maintained during the maturation to SP cells [103,113]. Similarly, expression of CCL25/TECKis strongest in the cortical epithelial cells that drive positive selection by selecting for thymocytes with TCRs capable of binding self-MHC [114],

6.3. Positive and Negative selection

During their maturation into DP cells, thymocytes undergo positive selection whereby cells with TCRs incapable of recognizing self-MHC are deleted [115]. Positively selected thymocytes migrate from the cortex to the CMJ where they interact with thymic antigen presenting cells (APCs) and undergo negative selection to eliminate thymocytes reactive with self MHC/peptide complexes on APCs [101]. Cell surface expression of CD69 is indicative of DP cells receiving a TCR signal [103], Several observations support a role for the chemokine receptor CCR4 in regulating the migration of positively selected CD4+CD8+ DP thymocytes through the negative selection process. The transition from CD69 to CD69+ cells coincides with responsiveness to the CCR4 ligand CCL22/MDC, as well as loss of responsiveness to CXCR4 [ 116,117]. This responsiveness is maintained as thymocytes progress through negative selection and first become CD4+ SP or CD8+ SP cells, but is lost as they progress to a more mature phenotype [116]. Expression of CCL22/macrophage-derived chemokine (MDC) by thymic epithelial cells and Hassal's corpuscles within the medulla suggests it recruits DP cells from the cortex into the medulla and it may play a role in negative selection [118]. CCL17/thymus and activation-regulated chemokine (TARC), another CCR4 and CCR8 ligand, is expressed by the thymic dendritic cells—which play a critical role in negative selection [119]. The role of other chemokine receptors and their ligands is less clear. CCL11/eotaxin and its receptor CCR3 may have a role in thymocyte negative selection since CCL11/eotaxin induces chemotaxis of DP and SP cells and CCR3 is expressed on thymic CD8+ SP cells [120,121], Similarly, the chemokines CCL18/PARC, CCL20/LARC, CXCL10/IP-10, CXCL11/I-TAC, CXCL9/MIG and their receptors CCR6 and CXCR3 are all expressed in the thymus but have not had their roles defined [103],

6.4. Exit from the thymus

Thymocytes which survive negative selection migrate deeper into the medulla where they reside for approximately 14 days and differentiate into mature CD4+ or CD8+ T cells before emigrating into the periphery [103], During this maturation, SP cells progress from a CD69+CD62L/ L-selectinl0 phenotype to a CD69 CD62L/L-selectinhi phenotype [103], Differentiation into CD69 CD62L/L-selectinhi cells is accompanied by a loss of responsiveness to the chemokine CCL25/TECK in CD4+ cells, but not CD8+ cells [122], The acquisition of a SP phenotype is also accompanied by expression of the chemokine receptor CCR7 [101,103,116]. Both CCR7 ligands CCL19/ELC and CCL21/SLC are expressed in the thymus with CCL19/ELC being localized to medullary stromal cells [101,123]. Mature T lymphocytes are then thought to exit the thymus via draining lymphatics and/or medullary vessels [103].

The role of chemokines in T lymphocytes exiting the thymus has been difficult to establish conclusively. Treatment with pertussis toxin - which inhibits chemokine receptor signalling - abrogates thymic emigration [124]. When coupled with the expression of CCL21/SLC in the draining vessels, this led to the proposition that CCR7 mediates thymic emigration [123]. However, CCR7' mice exhibit no apparent defect in thymocyte development and export, as the amount of peripheral CD4+ T cells increases by 6-fold [125]. In addition to a CCR7-mediated migration along a CCL21/SLC gradient, David Scadden's group proposed that T lymphocytes might in fact be moving along a decreased gradient of other chemotactic molecules [126]. This novel process, termed chemofugetaxis, has been demonstrated in an in vitro model of thymic emigration using mature SP cells and was blocked using antibodies to CXCL12/SDF-1. While this has yet to be confirmed in vivo, it suggests a possible model for not only thymic emigration, but lymphocyte movement out of secondary lymphoid tissues as well.

In summary, chemokines and chemokine receptors have definable roles in all stages of T cell development. One must be curious, however, about the lack of an obvious defect in T cell development within mice lacking CXCR4, CCR4, CCR7, or CCR9 receptors. This may be due to overlapping function and studies with multiple receptor knockouts must be pursued to confirm this hypothesis.

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