Mechanistic basis of pre–T cell receptor–mediated autonomous signaling critical for thymocyte development

Yamasaki, Sho; Ishikawa, Eri; Sakuma, Machie; Ogata, Koji; Sakata‐Sogawa, Kumiko; Hiroshima, Michio; Wiest, David L.; Tokunaga, Makio; Saito, Takashi

doi:10.1038/ni1290

Cited by 140 publications

(148 citation statements)

References 49 publications

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“…The constitutive activation of NF-B in DN thymocytes is thought to be mediated by pre-TCR, which is assembled after the rearrangement of TCR ␤-chain during the transition from DN3 to DN4 stages. Pre-TCR signaling is ligand-independent and may be initiated by the autonomous oligomerization of pre-TCR ␣-chain (38). However, the mechanism underlying the constitutive activation of NF-B at the SP stage is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Essential role of TAK1 in thymocyte development and activation

Liu¹,

Xie

Schneider

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

151

158

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The protein kinase TAK1 mediates the activation of NF-B in response to stimulation by proinflammatory cytokines and microbial pathogens in the innate immunity pathways. However, the physiological function of TAK1 in the adaptive immunity pathways is unclear. By engineering mice lacking TAK1 in T cells, here, we show that TAK1 is essential for thymocyte development and activation in vivo. Deletion of TAK1 prevented the maturation of single-positive thymocytes displaying CD4 or CD8, leading to reduction of T cells in the peripheral tissues. Thymocytes lacking TAK1 failed to activate NF-B and JNK and were prone to apoptosis upon stimulation. Our results provide the genetic evidence that TAK1 is required for the activation of NF-B in thymocytes and suggest that TAK1 plays a central role in both innate and adaptive immunity.T he Rel͞NF-B family of transcription factors regulates the expression of a plethora of genes involved in inflammation, immunity, and apoptosis (1, 2). NF-B is normally sequestered in the cytoplasm of unstimulated cells through its association with the I B family of inhibitory proteins. Stimulation of cells with a variety of agents leads to the rapid phosphorylation and subsequent degradation of I B by the ubiquitin-proteasome pathway, thus allowing NF-B to enter the nucleus to turn on various target genes.Phosphorylation of I B is catalyzed by a large kinase complex consisting of I B kinase (IKK)␣, IKK␤, and NEMO (also known as IKK␥ or IKKAP). The IKK complex integrates signals from diverse pathways, including those emanating from the receptors for TNF␣ and IL-1␤, Toll-like receptors (TLRs), and T cell receptors (TCRs) (3-6). Stimulation of IL-1R and some TLRs leads to the recruitment of several proteins, including the adaptor MyD88, the kinases IRAK4 and IRAK1, and the ubiquitin ligase TRAF6. TRAF6 functions in conjunction with the ubiquitin-conjugating enzyme (E2) complex Ubc13-Uev1A to catalyze the synthesis of Lys-63-linked polyubiquitin chains on certain protein targets, including TRAF6 itself (7,8). Polyubiquitinated TRAF6 activates a protein kinase complex consisting of the TAK1 kinase and the adaptor proteins TAB1 and TAB2 (8, 9). The activation of TAK1 by TRAF6 requires the binding between the K63 polyubiquitin chains and a conserved novel zinc finger (NZF) domain of TAB2 or its homologue TAB3 (10). After TAK1 is activated, it phosphorylates IKK␤ within the activation loop, resulting in the activation of IKK. TAK1 also phosphorylates and activates MKK6 and MKK7, leading to the activation of p38 and JNK kinase pathways.Recent studies have shown that TRAF-mediated polyubiquitination and the TAK1 kinase complex also play an important role in NF-B activation in T cells (11). Stimulation of TCR by an antigenic peptide and its cognate MHC activates a tyrosine kinase phosphorylation cascade, which, in turn, leads to the activation of protein kinase (PK)C . PKC then triggers the recruitment of the CARD domain proteins CARMA1 and BCL10 and the paracaspase MALT1 to lipid rafts (12)(13)(14). MALT1 ...

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Section: Discussionmentioning

confidence: 99%

Essential role of TAK1 in thymocyte development and activation

Liu¹,

Xie

Schneider

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

151

158

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“…The simplest explanation for these data would be to postulate that allelic exclusion is critically dependent upon pTa as long as TCRb expression levels remain within the physiological (for TCRVb3 Tg mice) or subphysiological (for TCRVb8.1 Tg mice) range. In cases where TCRb is highly overexpressed (such as in TCRVb8.2 Tg mice), one could speculate that pTa-independent TCRb:CD3 complexes reach a threshold level that is capable of partially inhibiting TCRb rearrangement, perhaps by favoring dimerization of CD3e, as recently reported for pTa [28].…”

Section: Discussionmentioning

confidence: 57%

A critical lineage‐nonspecific role for pTα in mediating allelic and isotypic exclusion in TCRβ‐transgenic mice

Ferrero¹,

Grosjean²,

Fiorini³

et al. 2007

Eur J Immunol

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Although it is well established that early expression of TCRb transgenes in the thymus leads to efficient inhibition of both endogenous TCRb and TCRc rearrangement (also known as allelic and "isotypic" exclusion, respectively) the role of pTa in these processes remains controversial. Here, we have systematically re-evaluated this issue using three independent strains of TCRb-transgenic mice that differ widely in transgene expression levels, and a sensitive intracellular staining assay that detects endogenous TCRVb expression in individual immature thymocytes. In the absence of pTa, both allelic and isotypic exclusion were reversed in all three TCRb-transgenic strains, clearly demonstrating a general requirement for pre-TCR signaling in the inhibition of endogenous TCRb and TCRc rearrangement. Both allelic and isotypic exclusion were pTa dose dependent when transgenic TCRb levels were subphysiological. Moreover, pTa-dependent allelic and isotypic exclusion occurred in both ab and cd T cell lineages, indicating that pre-TCR signaling can potentially be functional in cd precursors. Finally, levels of endogenous RAG1 and RAG2 were not down-regulated in TCRb-transgenic immature thymocytes undergoing allelic or isotypic exclusion. Collectively, our data reveal a critical but lineage-nonspecific role for pTa in mediating both allelic and isotypic exclusion in TCRb-transgenic mice. IntroductionT cells can be divided into ab and cd lineages based on their expression of TCRab or TCRcd. During development in the thymus, ab and cd lineages separate at an early CD4 -CD8 -double-negative (DN) stage, but the precise mechanism of lineage divergence remains controversial.One molecule that has been postulated to play a key role in ab/cd lineage commitment is the pTa chain. pTa is a critical component of the pre-TCR which consists, in addition, of a functionally rearranged TCRb chain and CD3 signaling components. Signaling through the pre-TCR has been reported to be responsible for many important functions during the development of ab lineage cells, including TCRb allelic exclusion [1-3], TCRc silencing [4], and extensive proliferation during the transition from DN to CD4 + CD8 + double-positive (DP) stages [5]. Since pTa -/-mice have an increased number of cd cells that harbor an increased frequency of in-frame TCRb rearrangements [6], it has also been proposed that the pre-TCR favors ab lineage commitment at the expense of cd cells [6]. Since functions of pTa are often difficult to study in normal mice, several groups have crossed pTa-deficient mice with TCRb-transgenic (Tg) mice to assess various putative roles for the pre-TCR during thymus development [7,8]. However, the results of these studies are in many cases controversial and it is still not known whether transgenic "artifacts" caused by overexpression or premature expression of the transgenic TCRb chain may obscure the contribution of pTa to the observed phenotypes.In order to re-evaluate this issue in a systematic manner, we have utilized three independent TCRb Tg mouse...

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“…It is thought that pre-TCR signaling in DN cells occurs autonomously in the absence of an extracellular ligand (44). This is in part facilitated by localization in lipid raft domains and by the tendency of pre-TCR␣-chains to dimerize, and perhaps by an inherent difference in the sensitivity of DN cells to respond to low potency signals (33,45,46). Our current data indicate that in addition to the pre-TCR, Lck is also relatively enriched within lipid raft membrane microdomains in DN compared with Lck in total thymocytes.…”

Section: Discussionmentioning

confidence: 99%

Changes in the Role of the CD45 Protein Tyrosine Phosphatase in Regulating Lck Tyrosine Phosphorylation during Thymic Development

Falahati

Leitenberg

2007

The Journal of Immunology

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CD45-dependent dephosphorylation of the negative regulatory C-terminal tyrosine of the Src family kinase Lck, promotes efficient TCR signal transduction. However, despite the role of CD45 in positively regulating Lck activity, the distinct phenotypes of CD45 and Lck/Fyn-deficient mice suggest that the role of CD45 in promoting Lck activity may be differentially regulated during thymocyte development. In this study, we have found that the C-terminal tyrosine of Lck (Y505) is markedly hyperphosphorylated in total thymocytes from CD45-deficient mice compared with control animals. In contrast, regulation of the Lck Y505 phosphorylation in purified, double-negative thymocytes is relatively unaffected in CD45-deficient cells. These changes in the role of CD45 in regulating Lck phosphorylation during thymocyte development correlate with changes in coreceptor expression and the presence of coreceptor-associated Lck. Biochemical analysis of coreceptor-associated and nonassociated Lck in thymocytes, and in cell lines varying in CD4 and CD45 expression, indicate that CD45-dependent regulation of Lck Y505 phosphorylation is most evident within the fraction of Lck that is coreceptor associated. In contrast, Lck Y505 phosphorylation that is not coreceptor associated is less affected by the absence of CD45. These data define distinct pools of Lck that are differentially regulated by CD45 during T cell development.

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Mechanistic basis of pre–T cell receptor–mediated autonomous signaling critical for thymocyte development

Cited by 140 publications

References 49 publications

Essential role of TAK1 in thymocyte development and activation

Essential role of TAK1 in thymocyte development and activation

A critical lineage‐nonspecific role for pTα in mediating allelic and isotypic exclusion in TCRβ‐transgenic mice

Changes in the Role of the CD45 Protein Tyrosine Phosphatase in Regulating Lck Tyrosine Phosphorylation during Thymic Development

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