Differential contribution of Lck and Fyn protein tyrosine kinases to intraepithelial lymphocyte development

Page, Stephanie T.; Oers, Nicolai S. C. van; Perlmutter, Roger M.; Weiss, Arthur; Pullen, Ann M.

doi:10.1002/eji.1830270229

Cited by 32 publications

(22 citation statements)

References 75 publications

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“…43 In addition, putative IEL precursors have been reported to express low levels of B220. 44,45 The similarity between this phenotype and that expressed in the population described here raises the possibility of a lineage relationship between these subsets. However, further investigations are required to formally assess this possibility.…”

Section: Discussionmentioning

confidence: 56%

Identification of the earliest prethymic bipotent T/NK progenitor in murine fetal liver

Douagi

Colucci

Santo

et al. 2002

Blood

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IntroductionMultipotent hematopoietic stem cells (HSCs) differentiate into precursors with increasingly restricted differentiation potential. This process, called lineage commitment, leads to the generation of oligopotent progenitors and finally to cells that are irreversibly engaged in a unique pathway of differentiation. The identification of progenitors at intermediate stages of differentiation is a fundamental step in understanding lineage commitment. The characterization of such intermediates within the erythromyeloid lineages has identified, in the bone marrow (BM), a granulocytemacrophage-restricted precursor and, more recently, a common myeloid precursor and an erythrocyte-megakaryocyte precursor. 1 T-cell generation occurs in the thymus from hematopoietic precursors present in fetal liver (FL) and adult BM. Although the pathways of intrathymic T-cell differentiation are relatively well characterized, the role of the thymic microenvironment as a unique site for the induction of commitment to the T-cell lineage remains a matter of debate. 2,3 Moreover, the identification of T-cell progenitors before thymic colonization remains incomplete. Cells endowed with a nonrestricted potential of differentiation into T lymphocytes have been phenotypically characterized and isolated from adult BM. Thus, HSCs as well as common lymphoid progenitors (CLPs) were purified. 4,5 The existence of committed T-cell precursors (TCPs) in the BM 6 and more recently in the FL has been suggested. 7,8 However, the identification of surface markers allowing the isolation of these cells has not been achieved. Populations of precursors restricted to the T-cell and natural killer cell (NK) lineages have been reported in fetal thymus, blood, and spleen. [9][10][11][12][13] In 2 independent studies, T and NK precursors have been characterized in fetal thymus either as Fc␥RII/III ϩ9 or as CD90 ϩ NK1.1 ϩ CD117 ϩ , 11 although the total number of precursors present at these sites was not evaluated.We and others have previously reported that the FL, the major hematopoietic organ during embryonic life, provides TCPs with restricted potential of differentiation that continuously colonize the fetal thymus. [14][15][16] In an attempt to identify such intermediate precursors, we isolated different fractions of FL cells and analyzed them in a quantitative manner for lymphocyte precursor activity.Here we identify a novel population corresponding to 0.2% of FL cells that includes the majority (70%) of TCPs in this organ. These cells retained the capacity to differentiate into both T and NK progeny at the single-cell level. When transferred in vivo, they reconstituted the peripheral T and NK compartments and gave rise to intraepithelial T cells of extrathymic origin. This cell population, designated here as common T/NK cell progenitor (C-TNKP), differs both by surface marker and by gene expression analysis from previously described bipotent T/NK precursors present in fetal blood, spleen, and thymus. We propose that these cells represent the immediate ...

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Section: Discussionmentioning

confidence: 56%

Identification of the earliest prethymic bipotent T/NK progenitor in murine fetal liver

Douagi

Colucci

Santo

et al. 2002

Blood

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“…Remarkably, these TCR Ϫ IEL did not appear to contain the CD8␣␣ ϩ subset. Thus, the absence of TCR Ϫ CD8␣␣ ϩ IEL in athymic CR␥ Ϫ/Y mice contrasts sharply with the phenotype of putative TCR Ϫ IEL precursors present in young wild-type (WT) (19), athymic (nu/nu) nude (9), SCID (9,33), RAG-1 Ϫ/Ϫ (23,24), lck Ϫ/Ϫ ϫ fyn Ϫ/Ϫ (23), CD3 Ϫ/Ϫ (24), and CD3⑀ Ϫ/Ϫ (24) mice, a predominant fraction of which expresses the CD8␣␣ homodimer.…”

Section: N Umerous Intraepithelial T Cells (Iel)mentioning

confidence: 98%

“…Accumulating evidence indicates that these CD8␣␣ ϩ IEL are potentially capable of developing somewhere in the intestinal mucosa without passing through the thymus (9,(15)(16)(17)(18)(19)(20). Moreover, the presence of lymphoid cells with properties of precursor T cells among IEL (1,9,19,(21)(22)(23)(24) and the expressions of recombination activating gene-1 (RAG-1) (9,19,21) and RAG-2 (25) by a subset of IEL support the notion that T lineage-committed precursors may enter the epithelium and undergo all steps of TCR gene rearrangement and subsequent differentiation into mature IEL in situ.…”

Section: N Umerous Intraepithelial T Cells (Iel)mentioning

confidence: 99%

Role of Gut Cryptopatches in Early Extrathymic Maturation of Intestinal Intraepithelial T Cells

Oida

Suzuki

Nanno

et al. 2000

The Journal of Immunology

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Lympho-hemopoietic progenitors residing in murine gut cryptopatches (CP) have been shown to generate intestinal intraepithelial T cells (IEL). To investigate the role of CP in progenitor maturation, we analyzed IEL in male mice with a truncated mutation of common cytokine receptor γ-chain (CRγ−/Y) in which CP were undetectable. IEL-expressing TCR-γδ (γδ-IEL) were absent, and a drastically reduced number of Thy-1highCD4+ and Thy-1highCD8αβ+ αβ-IEL were present in CRγ−/Y mice, whereas these αβ-IEL disappeared from athymic CRγ−/Y littermate mice. Athymic CRγ−/Y mice possessed a small TCR- and αEβ7 integrin-negative IEL population, characterized by the disappearance of the extrathymic CD8αα+ subset, that expressed pre-Tα, RAG-2, and TCR-Cβ but not CD3ε transcripts. These TCR− IEL from athymic CRγ−/Y mice did not undergo Dβ-Jβ and Vδ-Jδ joinings, despite normal rearrangements at the TCR-β and -δ loci in thymocytes from euthymic CRγ−/Y mice. In contrast, athymic severe combined immunodeficient mice in which CP developed normally possessed two major TCR−αEβ7+ CD8αα+ and CD8− IEL populations that expressed pre-Tα, RAG-2, TCR-Cβ, and CD3ε transcripts. These findings underscore the role of gut CP in the early extrathymic maturation of CD8αα+ IEL, including cell-surface expression of αEβ7 integrin, CD3ε gene transcription, and TCR gene rearrangements.

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“…The present study revealed that Syk-dependent γδTCR signals are indispensable for the thymic maturation and acquisition of the effector function of γδT cells. It has been demonstrated that the TCR signaling machinery differs between αβT and γδT cells (17)(18)(19)(20)(21)(22)(23)40), although these 2 cell types derive from common progenitors in the thymus. We showed here that in ex vivo γδT cells, engagement of the γδTCR-CD3 complex leads to the phosphorylation of Syk and Zap70.…”

Section: Pik3cdmentioning

confidence: 99%

“…αβT and γδT cells also show differential requirements of the Src family kinases in their development. In Lck/ Fyn-doubly deficient mice, αβT cell development is completely inhibited, whereas γδT cell development is partially impaired (21,22). Moreover, γδT cells require Blk, an Src family kinase primarily expressed in B cells, for the induction of the γδT17 subset (23).…”

Section: Introductionmentioning

confidence: 99%

γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program

Muro¹,

Nitta²,

Nakano³

et al. 2017

Journal of Clinical Investigation

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Results Preferential requirement of Syk rather than Zap70 in γδTCR signalsand γδT cell development. To characterize the intracellular signal γδT cells produce inflammatory cytokines and have been implicated in the pathogenesis of cancer, infectious diseases, and autoimmunity. The T cell receptor (TCR) signal transduction that specifically regulates the development of IL-17-producing γδT (γδT17) cells largely remains unclear. Here, we showed that the receptor proximal tyrosine kinase Syk is essential for γδTCR signal transduction and development of γδT17 in the mouse thymus. Zap70, another tyrosine kinase essential for the development of αβT cells, failed to functionally substitute for Syk in the development of γδT17. Syk induced the activation of the PI3K/Akt pathway upon γδTCR stimulation. Mice deficient in PI3K signaling exhibited a complete loss of γδT17, without impaired development of IFN-γ-producing γδT cells. Moreover, γδT17-dependent skin inflammation was ameliorated in mice deficient in RhoH, an adaptor known to recruit Syk. Thus, we deciphered lineage-specific TCR signaling and identified the Syk/PI3K pathway as a critical determinant of proinflammatory γδT cell differentiation.

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Differential contribution of Lck and Fyn protein tyrosine kinases to intraepithelial lymphocyte development

Cited by 32 publications

References 75 publications

Identification of the earliest prethymic bipotent T/NK progenitor in murine fetal liver

Identification of the earliest prethymic bipotent T/NK progenitor in murine fetal liver

Role of Gut Cryptopatches in Early Extrathymic Maturation of Intestinal Intraepithelial T Cells

γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program

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