Factors that influence the thymic selection of CD8αα intraepithelial lymphocytes

ABSTRACTThymocytes bearing αβ T cell receptors (TCRαβ) with high affinity for self-peptide-MHC complexes undergo negative selection or are diverted to alternate T cell lineages, a process termed agonist selection. Among thymocytes bearing TCRs restricted to MHC class I, agonist selection can lead to the development of precursors that can home to the gut and give rise to CD8αα-expressing intraepithelial lymphocytes (CD8αα IELs). The factors that influence the choice between negative selection versus CD8αα IEL development remain largely unknown. Using a synchronized thymic tissue slice model that supports both negative selection and CD8αα̣IEL development, we show that the affinity threshold for CD8αα IEL development is higher than for negative selection. We also investigate the impact of peptide presenting cells and cytokines, and the migration patterns associated with these alternative cell fates. Our data highlight the roles of TCR affinity and the thymic microenvironments on T cell fate.

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Evidence for the divergence of innate and adaptive T-cell precursors before commitment to the αβ and γδ lineages

Blood ◽

10.1182/blood-2011-05-352732 ◽

2011 ◽

Vol 118 (25) ◽

pp. 6591-6600 ◽

Cited By ~ 21

Author(s):

Jan Kisielow ◽

Luigi Tortola ◽

Jacqueline Weber ◽

Klaus Karjalainen ◽

Manfred Kopf

Keyword(s):

T Cells ◽

T Cell ◽

Natural Killer ◽

Negative Selection ◽

Intraepithelial Lymphocytes ◽

Lineage Commitment ◽

Γδt Cells ◽

Cell Lineages ◽

Innate T Cells ◽

Tcr Signals

Abstract In addition to adaptive T cells, the thymus supports the development of unconventional T cells such as natural killer T (NKT) and CD8αα intraepithelial lymphocytes (IELs), which have innate functional properties, particular antigenic specificities, and tissue localization. Both conventional and innate T cells are believed to develop from common precursors undergoing instructive, TCR-mediated lineage fate decisions, but innate T cells are proposed to undergo positive instead of negative selection in response to agonistic TCR signals. In the present study, we show that, in contrast to conventional αβT cells, innate αβT cells are not selected against functional TCRγ rearrangements and express TCRγ mRNA. Likewise, in contrast to the majority of γδT cells, thymic innate γδT cells are not efficiently selected against functional TCRβ chains. In precursors of conventional T cells, autonomous TCR signals emanating from the pre-TCR or γδTCR in the absence of ligand mediate selection against the TCR of the opposite isotype and αβ/γδ lineage commitment. Our data suggest that developing innate T cells ignore such signals and rely solely on agonistic TCR interactions. Consistently, most innate T cells reacted strongly against autologous thymocytes. These results suggest that innate and adaptive T-cell lineages do not develop from the same pool of precursors and potentially diverge before αβ/γδ lineage commitment.

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Cell movements and cell fate during zebrafish gastrulation

Development ◽

10.1242/dev.116.supplement.65 ◽

1992 ◽

Vol 116 (Supplement) ◽

pp. 65-73 ◽

Cited By ~ 6

Author(s):

Robert K. Ho

Keyword(s):

Single Cell ◽

Cell Fate ◽

Fate Map ◽

Cell Fates ◽

Cell Lineages ◽

Cell Position ◽

Vertebrate Embryo ◽

Cellular Identity ◽

Transplantation Experiments

The early lineages of the zebrafish are indeterminate and a single cell labeled before the late blastula period will contribute progeny to a variety of tissues. Therefore, early cell lineages in the zebrafish do not establish future cell fates and early blastomeres must necessarily remain pluripotent. Eventually, after a period of random cell mixing, individual cells do become tissue restricted according to their later position within the blastoderm. The elucidation of a fate map for the zebrafish gastrula (Kimmel et al., 1990), has made it possible to study the processes by which cellular identity is conferred and maintained in the zebrafish. In this chapter, I describe single cell transplantation experiments designed to test for the irreversible restriction or ‘commitment’ of embryonic blastomeres in the zebrafish embryo. These experiments support the hypothesis that cell fate in the vertebrate embryo is determined by cell position. Work on the spadetail mutation will also be reviewed; this mutation causes a subset of mesodermal precursors to mismigrate during gastrulation thereby leading to a change in their eventual cell identity.

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