Characterization of T Cell Differentiation in the Murine Gut

Lambolez, Florence; Azogui, Orly; Joret, Anne‐Marie; Garcia, Cyrielle; Boehmer, Harald von; Santo, James P. Di; Ezine, Sophie; Rocha, Bénédita

doi:10.1084/jem.20010798

Cited by 85 publications

(141 citation statements)

References 53 publications

(106 reference statements)

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“…Our previous ontogenetic study suggested that this seeding takes place during the first few weeks of life [10]. As mentioned above, a thymic origin of such diversity appears highly likely because local differentiation in the gut mucosa would not be sufficiently effective [14]. Our data also oppose the notion of a strict origin of CD8ab + IEL from a few recirculating random Agstimulated peripheral CD8 + T lymphoblasts [17], as this would not generate the diversity observed here in GF animals.…”

Section: Discussioncontrasting

confidence: 55%

“…The murine cryptopatches appear later in ontogeny, around weaning. Although the limited T cell generative capacity of the cryptopatches [13,14] has been taken to explain why CD8aa + IEL are oligoclonal [14], other studies have provided evidence for selection of CD8aa + IEL precursors in the thymus rather than in the cryptopatches [15,16]. Conversely, oligoclonality of CD8ab + IEL reportedly results from random emergence in thoracic duct lymph of a few pre-activated peripheral CD8 + T cells that are subsequently distributed to the gut epithelium [17], but this hypothesis cannot account for the broad CD8 IEL repertoires observed in the present study.…”

Section: Introductionmentioning

confidence: 99%

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Microbial colonization induces oligoclonal expansions of intraepithelial CD8 T cells in the gut

et al. 2004

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Two populations of CD8+ IEL generally express restricted, but apparently random and nonoverlapping TCR repertoires. Previous studies in mice suggested that this could be explained by a dual origin of CD8 + IEL, i.e. that CD8ab + IEL derive from a few peripheral CD8 + T cell lymphoblasts stimulated by microbial antigens in gut-associated lymphoid tissue, whereas CD8aa + IEL descend from an inefficient intestinal maturation pathway. We show here that the gut mucosa, instead, becomes seeded with surprisingly broad and generally nonoverlapping CD8 IEL repertoires and that oligoclonality is induced locally after microbial colonization. In germ-free (GF) rats, both CD8ab + and CD8aa + IEL displayed surprisingly diverse TCR Vb repertoires, although b-chain diversity tended to be somewhat restricted in the CD8aa + subset. CDR3 length displays in individual Vb-Cb and Vb-Jb combinations generally revealed polyclonal distributions over 6-11 different lengths, similar to CD8 + lymph node T cells, and CDR3b sequencing provided further documentation of repertoire diversity. By contrast, in ex-GF rats colonized with normal commensal microflora, both CD8ab + and CD8aa + IEL displayed oligoclonal CDR3 length distributions for most of the Vb genes analyzed. Our data suggest that microbial colonization induces apparently random clonal expansions of CD8ab + and CD8aa + IEL locally in the gut.

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Section: Discussioncontrasting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Microbial colonization induces oligoclonal expansions of intraepithelial CD8 T cells in the gut

et al. 2004

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“…Previous studies using pTa ic staining [6], single-cell PCR [19] and reporter mice [20] are consistent with the possibility that most DN3 thymocytes, which have recently been shown to contain a very small subset of cd precursors [21], express pTa. However, no functional evidence for the presence of pTa in cd precursors has been reported.…”

Section: Tcrb Transgenes Mediate Pta-dependent Allelic Exclusion In Csupporting

confidence: 59%

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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“…Third, some IELs can recognize and respond to nonclassical major histocompatibility complex molecules [3,4] and heat shock proteins [5], which may be linked to CD8αα expression by IELs. Fourth, the mammalian intestine can promote the differentiation of T cell precursors from bone marrow progenitors [6][7][8], and the intestine appears to provide both contactmediated and humoral components necessary for the maturation of T cells [9]. Consistent with that, developing IELs have receptors for IL-7 and use IL-7 for survival and maturation [10,11].…”

Section: Introductionmentioning

confidence: 79%

Intestinal TSH production is localized in crypt enterocytes and in villus ‘hotblocks’ and is coupled to IL-7 production: evidence for involvement of TSH during acute enteric virus infection

et al. 2005

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The immune and neuroendocrine systems have been shown to work conjointly in a number of ways. One aspect of this has to do with a potential role for thyroid stimulating hormone (TSH) in the regulation of the mucosal immune system, although the mechanisms by which this occurs remain vague. To more thoroughly understand how TSH participates in intestinal intraepithelial lymphocyte (IEL) development and immunity, experiments have been conducted to define local sites of intestinal TSH production, and to characterize changes that occur in the synthesis of TSH during acute enteric virus infection. Here, we demonstrate that TSH in the small intestine is specifically localized to regions below villus crypts as seen by immunocytochemical staining, which revealed high-level TSH staining in lower crypts in the absence of IL-7 staining, and TSH and IL-7 costaining in upper crypt regions. Additionally, prominent TSH staining was evident in TSH 'hotblocks' sparsely dispersed throughout the epithelial layer. In rotavirus-infected mice, the TSH staining pattern differed significantly from that of non-infected animals. Notably, at 2 and 3 days post-infection, TSH expression was high in and near apical villi where virus infection was greatest. These findings lend credence to the notion that TSH plays a role both in the development of intestinal T cells, and in the process of local immunity during enteric virus infection.

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Characterization of T Cell Differentiation in the Murine Gut

Cited by 85 publications

References 53 publications

Microbial colonization induces oligoclonal expansions of intraepithelial CD8 T cells in the gut

Microbial colonization induces oligoclonal expansions of intraepithelial CD8 T cells in the gut

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

Intestinal TSH production is localized in crypt enterocytes and in villus ‘hotblocks’ and is coupled to IL-7 production: evidence for involvement of TSH during acute enteric virus infection

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