Towards a molecular understanding of the differential signals regulating αβ/γδ T lineage choice

Immune Cell Development and Host Defense Program, Blood Cell Development and Cancer Keystone, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Seminars in Immunology (Impact Factor: 5.17). 08/2010; 22(4):237-46. DOI: 10.1016/j.smim.2010.04.008
Source: PubMed


While insights into the molecular processes that specify adoption of the alphabeta and gammadelta fates are beginning to emerge, the basis for control of specification remains highly controversial. This review highlights the current models attempting to explain T lineage commitment. Recent observations support the hypothesis that the T cell receptor (TCR) provides instructive cues through differences in TCR signaling intensity and/or longevity. Accordingly, we review evidence addressing the importance of differences in signal strength/longevity, how signals differing in intensity/longevity may be generated, and finally how such signals modulate the activity of downstream effectors to promote the opposing developmental fates.

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Available from: David L Wiest
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    • "Our findings, and those of others, demonstrate that expression of TCR alone is not sufficient to dictate the lineage fate of progenitors (Lee et al., 2010); however, to date, aside from the absence of development to the DP stage, there is no other marker that distinguishes DN TCR-expressing cells that have adopted the  fate from those that have yet to do so. To identify such markers, we performed microarray analysis to reveal genes that are highly expressed, compared with  lineage DP cells, in both KN6 TCR Tg thymocytes that are adopting the  fate in response to ligand engagement and in polyclonal non-Tg TCR-expressing cells. "
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    • "ab T cells are located primarily in secondary lymphoid organs, recognize peptides in association with MHC I and II, and respond by facilitating the production of Ab or by lysing infected target cells. g d T cells represent a small percent of cells in the thymus and secondary lymph tissue, are abundant at epithelial surfaces and use fewer gene segments (to encode the TCR) to recognize a wider variety of Ags, including non-classical MHCs, heat shock proteins, and lipids (Lee et al., 2010). Some g d T cells appear to recognize Ag without presentation (Murphy et al., 2008). "
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    • "performed WISH on morphants at 5 dpf using probes identifying important regulators of T cell development (Figure 3). These probes include: (1) foxn1, a transcription factor required for generation of thymic epithelium (Su et al., 2003), (2) ikaros, a DNA-binding protein required for lymphoid development (Georgopoulos et al., 1997), (3) rag1, a lymphocytespecific nuclease required for T cell antigen receptor (TCR) gene rearrangement, (4) lck, a tyrosine kinase required for T cell development (Langenau et al., 2004), and (5) TCRb (tcrb) and TCRd (tcrd) subunits that identify ab-lineage and gd-lineage progenitors, respectively (Lee et al., 2010). WISH using probes marking T lineage progenitors (Figure 3A; ikaros, rag1) revealed that knockdown of Rpl22 did not impair seeding of the thymus; however, it did impair progenitor development and expansion as indicated by the reduced staining with probes that mark more mature progeny (Figure 3A; lck, tcrb). "
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    ABSTRACT: It remains controversial whether the highly homologous ribosomal protein (RP) paralogs found in lower eukaryotes have distinct functions and this has not been explored in vertebrates. Here we demonstrate that despite ubiquitous expression, the RP paralogs, Rpl22 and Rpl22-like1 (Rpl22l1) play essential, distinct, and antagonistic roles in hematopoietic development. Knockdown of Rpl22 in zebrafish embryos selectively blocks the development of T lineage progenitors after they have seeded the thymus. In contrast, knockdown of the Rpl22 paralog, Rpl22l1, impairs the emergence of hematopoietic stem cells (HSC) in the aorta-gonad-mesonephros by abrogating Smad1 expression and the consequent induction of essential transcriptional regulator, Runx1. Indeed, despite the ability of both paralogs to bind smad1 RNA, Rpl22 and Rpl22l1 have opposing effects on Smad1 expression. Accordingly, circumstances that tip the balance of these paralogs in favor of Rpl22 (e.g., Rpl22l1 knockdown or Rpl22 overexpression) result in repression of Smad1 and blockade of HSC emergence.
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