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The Journal of Immunology, 2000, 165: 5397-5400.
Copyright © 2000 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: An Essential Role for Notch-1 in the Development of Both Thymus-Independent and -Dependent T Cells in the Gut1

Anne Wilson, Isabel Ferrero, H. Robson MacDonald2 and Freddy Radtke

Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Whereas most T cells arise in the thymus, a distinct lineage of extrathymically derived T cells is present in the gut mucosa. The developmental origin of extrathymic T cells is poorly understood. We show here that Notch-1, a transmembrane receptor involved in T cell fate specification of bipotential T/B precursors in the thymus, is absolutely required for the development of extrathymic (as well as thymus-derived) mature T cells in the intestinal epithelium. In the absence of Notch-1, CD117+ T cell precursors are relatively more abundant in the gut than the thymus, whereas immature B cells accumulate in the thymus but not the gut. Collectively, these data demonstrate that Notch-1 is essential for both thymic and extrathymic T cell fate specification and further suggest that bipotential T/B precursors that do not receive a Notch-1 signal adopt a B cell fate in the thymus but become developmentally arrested in the gut.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
While the majority of T lymphocytes in primary and secondary lymphoid organs are dependent upon the thymus for their development, a distinct lineage of extrathymically derived T cells is present in the epithelium of the intestinal mucosa. Thymus-independent (TI)3 intestinal intraepithelial lymphocytes (iIEL), can express either an {alpha}{beta} TCR or a {gamma}{delta} TCR and differ from their thymus-dependent (TD) iIEL counterparts in that they fail to express several phenotypic markers characteristic of mature T cells (including Thy-1 or CD90, CD5, and CD28) and express a homodimeric form of the CD8{alpha} coreceptor in contrast to the CD8{alpha}{beta} heterodimer expressed by conventional CD8+ T cells (1, 2, 3, 4).

In addition to phenotypic differences, TI-iIEL differ from thymus-derived T cells in their TCR-associated signaling components. Thus whereas conventional T cells have CD3{zeta} homodimers associated with their TCR, TI- iIEL have TCR-associated heterodimers composed of CD3{zeta} and Fc{epsilon}RI{gamma} (a CD3{zeta} homologue) (5). This difference is developmentally relevant because TI-iIEL (but not conventional T cells) expressing either an {alpha}{beta} TCR or a {gamma}{delta} TCR develop normally in gene-targeted CD3{zeta}-deficient mice (6, 7).

Consistent with their unique TCR-associated signaling components, TI-iIEL show distinct requirements for positive and negative selection as compared with thymus-derived T cells. For example, whereas conventional TCR {alpha}{beta}+ CD8{alpha}{beta} T cells are positively selected by classical MHC class I molecules and negatively selected by self Ags in the thymus, TCR {alpha}{beta}+ CD8{alpha}{alpha} TI-iIEL are positively selected by nonclassical MHC class Ib (8, 9, 10) and apparently do not undergo negative selection (11, 12, 13). The selection requirements for TCR {gamma}{delta}+ T cells (whether of thymic or extrathymic origin) remain obscure.

Although the site of generation of TI-iIEL remained controversial for some time, two recent studies strongly suggest that the gut epithelium itself provides the inductive microenvironment necessary for extrathymic T cell development. Thus Saito et al. (14) isolated CD117+ lineage-negative (lin-) precursor cells from specialized intestinal structures (termed cryptopatches) in the lamina propria of athymic mice and showed that they gave rise to TI-iIEL progeny when transferred into SCID recipients. In a different approach, Laky et al. (15) showed that tissue-specific expression of IL-7 in enterocytes of IL-7-deficient mice led to the development of TCR {gamma}{delta}+ iIEL in the intestine but not in any other tissue. Taken together, these reports provide compelling evidence that extrathymic T cell development can occur in situ in the intestinal epithelium.

Despite the fact that clear-cut differences in surface phenotype, TCR structure, and selection requirements between TI-iIEL and conventional T cells have been described, it is not clear whether the basic mechanisms controlling T cell fate specification differ in the thymus and the gut. In this respect, we have recently reported that Notch-1, a member of the Notch multigene family that controls binary cell fate decisions in several developmental systems (16, 17), is absolutely required for the development of all conventional T cells in the thymus as well as secondary lymphoid organs such as lymph nodes and spleen (18). In this report, we have used a competitive bone marrow (BM) reconstitution system to demonstrate that extrathymic T cell development in the gut is also totally Notch-1 dependent. We conclude that Notch-1 signaling plays a selective but essential role in T cell fate specification both in the thymus and in extrathymic tissues such as the intestinal epithelium.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Inducible Notch-1-deficent mice and competitive mixed BM chimeras

Notch-1lox/lox and Notch-1lox/lox/Mx-Cre mice as well as competitive mixed BM chimeras were generated as previously described (18). All BM donors were treated with poly(I:C) (an inducer of endogenous IFN-{alpha}). Deletion of Notch-1 was >98% as assessed by Southern blot analysis of Notch-1lox/lox/Mx-Cre BM.

Isolation of iIEL and intestinal lamina propria lymphocytes (iLPL)

iIELs and iLPLs were isolated from individual mice by standard methods (15). Briefly, 6-wk-old C57BL/6 mice (Harlan, Olac, U.K.) were sacrificed, and their small intestines were removed into cold PBS. Peyer’s patches were removed by dissection under a strong light over a black surface. The intestines were then opened longitudinally, flushed with cold PBS to remove detritus, cut into 1-cm pieces, and washed two times in Ca2+- and Mg2+-free HBSS (Life Technologies, Rockville, MD) supplemented with 2% horse serum (HS) (Life Technologies). Each intestine was then incubated two times in 50 ml HBSS/1 mM HEPES/1 mM DTT/2.5 mM NaHCO3/10% HS for 20 min at 37°C with constant stirring in a bottle precoated with HS to minimize cell loss by adhesion. Cells released into the supernatant were harvested by filtration through a sieve and washed one time in HBSS/HEPES/5% HS. The lymphocyte fraction was subsequently recovered by centrifugation at 900 x g for 15 min through a Percoll (Amersham Pharmacia Biotech, Uppsala, Sweden) gradient (5 ml 44% Percoll layered over 5 ml 67.5% Percoll) at room temperature. After harvesting the lymphocyte fraction at the interface, the cells were washed two times in HBSS/5% HS before use. iLPL were prepared from the pieces of gut left over from the iIEL isolation after extensively washing (two times 30 min at 37°C in HBSS/1.3 mM EDTA) to remove any residual iIELs. After 20 min at room temperature in RPMI 1640/5% HS, the fragments were digested two times with 100 U/ml Collagenase (Sigma, St. Louis, MO) in RPMI 1640/1 mMCaCl2/1 mM MgCl2/5% HS for 30 min at 37°C. The supernatant was collected each time, and the cells were washed in PBS/5% FCS. The lymphocyte fraction was subsequently isolated over a Percoll gradient as for iIEL.

Abs, FACS staining, and analysis

Cell suspensions were stained and analyzed by FACS as described previously (18). Briefly, after isolation of iIELs or iLPLs (see above), cells were stained in the presence of 2.4.G.2 supernatant (anti-FcR mAb) for four-color FACS analysis. The following mAb conjugates were used: anti-CD4-CyChrome, anti-CD8{alpha}-CyChrome, anti-B220-CyChrome, anti-B220-FITC, anti-CD117-PE, anti-CD3{epsilon}-PE, anti-CD19-PE, and anti-CD45.2-PE (PharMingen, San Diego, CA); anti-CD45.1-Cy5 and anti-CD45.2-Cy5 were conjugated in this laboratory from purified protein purchased from PharMingen; anti-CD8{beta}-FITC, anti-CD8{alpha}-FITC, anti-CD4-FITC, and anti-CD3{epsilon}-FITC were purified and conjugated in this laboratory. Cells were analyzed on a FACScalibur flow cytometer using CellQuest software (Becton Dickinson, San Jose, CA). Live gating was performed to eliminate dead cells and debris from the analysis, and data from 200,000 cells were collected for each file.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To determine whether extrathymic (as well as thymic) T cell development is Notch-1 dependent, the development of T cells in the intestinal mucosa was assessed in inducible Notch-1-deficient mice. Because the deletion efficiency of the floxed Notch-1 gene (mediated by an IFN-{alpha}-inducible Cre recombinase transgene) is only around 60% in the gut but close to 100% in the BM of these mice (18), a competitive mixed BM chimera system was employed. CD45.2+ BM from either Notch-1-deleted (Notch-1lox/lox/Mx-Cre) or control (Notch-1lox/lox) mice was mixed at a 2:1 ratio with CD45.1+ wild-type BM and injected into CD45.1+ lethally irradiated C57BL/6 mice to give Notch-1-deleted or control chimeras, respectively. CD45.2+ donor-derived iIEL from individual mice were analyzed after 3–6 mo. As shown in Fig. 1GoA, both control and Notch-1-deleted BM were able to reconstitute the lymphoid component of the gastrointestinal tract to a similar extent. After gating on donor-derived CD45.2+ cells, both CD4+ and CD8{alpha}{beta}+ TD-iIEL subsets can be detected in control chimeras; however, virtually no TD-iIEL can be detected derived from Notch-1-deleted BM. In absolute cell numbers, this represents a 15-fold decrease in CD4+ and a 13-fold decrease in CD8{alpha}{beta}+ TD-iIEL (Fig. 2Go). As expected, both CD4+ and CD8{alpha}{beta}+ cells can be detected among CD45.1+ iIEL derived from wild-type BM in all chimeric mice in equivalent numbers (data not shown). This finding confirms and extends our previous results (18) by showing that Notch-1 is essential for the development of thymus-derived T cells in the gut as well as in other organs.



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  		FIGURE 1. A, No TD-iIEL are produced from Notch-1-deficient BM. Intestinal IEL prepared from mixed BM chimeras were stained for the extent of chimerism with anti-CD45.1 and anti-CD45.2 mabs (top panel). After gating on CD45.2+ cells expression of CD8{beta} vs CD4 (bottom panel) in both control and Notch-1-deleted iIEL is shown. B, Expression of CD19 on CD45.2+ iIEL after gating out all conventional T cells with a pool of mAbs recognizing CD4 and CD8{beta}.

 


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  		FIGURE 2. Absolute numbers of TD-iIEL and TI-iIEL in the CD45.2+ fraction of mixed BM chimeras. {square}, Control; {blacksquare}, Notch-1 deleted. Results are mean ± SD of 6 (control) and 13 (Notch-1 deleted) individual mice.

 
TI-iIEL can be identified by their expression of a CD8{alpha}{alpha} homodimer instead of the more conventional CD8{alpha}{beta} heterodimer (19, 20). Both TCR {alpha}{beta}+ and TCR {gamma}{delta}+ T cells can express the homodimeric CD8 molecule. Fig. 3Go shows the expression of CD8{alpha} vs CD3{epsilon} on CD45.2+ iIEL after gating out thymus-dependent (i.e., CD4+ and CD8{alpha}{beta}+) cells in control or Notch-1-deleted chimeras. In control chimeras, a substantial percentage of CD8{alpha}{alpha}+ TI-iIEL was observed. These CD8{alpha}{alpha}+ cells expressed CD3{epsilon} (Fig. 3Go) and comprised a mixture of TCR {alpha}{beta}+ and TCR {gamma}{delta}+ cells (data not shown). In contrast, no CD8{alpha}{alpha}+ or CD3{epsilon}+ TI-iIEL were detected in Notch-1-deficient chimeras (Fig. 3Go). The absolute magnitude of the decrease in TI-iIEL in Notch-1-deleted chimeras was 10- to 15-fold for both TCR {alpha}{beta}+ and TCR {gamma}{delta}+ cells (Fig. 2Go), which is in the same range as for TD (CD4+ and CD8{alpha}{beta}+) iIEL subsets. These results clearly demonstrate that the development of both thymic and extrathymically derived gut T cells is Notch-1 dependent.



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  		FIGURE 3. TI-iIEL are absent in Notch-1-deleted mixed BM chimeras. CD45.2+ iIEL from control or Notch-1-deleted mixed BM chimeras were stained with mAbs to CD3{epsilon} and CD8{alpha} after gating out conventional TD-iIEL with a pool of mAbs against CD4 and CD8{beta}.

 
In a previous study, we showed that a population of immature B cells of Notch-1-/- origin accumulated in the thymus instead of T cells, suggesting that Notch-1 controls a binary T/B lineage decision of a common lymphoid precursor (18). If the gut microenvironment is permissive for B cell development, we might expect to find a similar population of immature B cells accumulating in the intestine. However, although a relative increase in the percentage of CD19+ cells was observed within the CD45.2+ iIEL population of Notch-1-deficient origin as compared with CD45.2+ iIEL derived from control BM (Fig. 1GoB), no increase in total B cell numbers was observed (Fig. 2Go). In addition, no difference in the expression of B220, IgM, CD5, CD43, or MHC class II was detected between intestinal B cells in both types of chimeras originating from Notch-1-deficient or control precursors (data not shown). Indeed, the phenotype of intestinal B cells in both the IEL and LPL compartments was very similar to that of circulating mature B cells and clearly distinct from immature BM B cells (data not shown). Thus whereas the thymus microenvironment appears to allow limited maturation of immature B cell precursors (18, 21), ectopic B cell development in the gut may not be possible.

CD117+ lin- cells located in cryptopatches of the gut lamina propria have been described as potential precursor cells for TI-IELs (14, 22). Therefore, expression of CD117 on lin- (CD3-4-8{beta}-B200-) cells derived from control or Notch-1-deficient BM was examined in the intestinal epithelium and lamina propria of mixed BM chimeras. Interestingly the percentage of CD117+ lin- cells among iIEL or iLPL derived from control or Notch-1-deficient BM was not significantly different (Fig. 4GoA) and absolute cell numbers of Notch 1-/- CD117+ lin- iIEL and iLPL were only reduced 2-fold (Fig. 4GoB). In contrast, CD117+ lin- (CD3-4-8{alpha}-) thymocytes derived from Notch-1-deficient BM were reduced 9-fold as compared with control BM in the same mixed chimeras (Fig. 4GoB). These data indicate that CD117+ lin- precursors of Notch-1-/- origin are relatively more abundant in the gut than in the thymus, despite the complete absence of mature T cells in both tissues. Moreover, the presence of CD117+ lin- cells in both the thymus and intestine essentially rule out defective homing of T cell precursors as an explanation for the absence of mature T cells of Notch-1-/- origin.



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  		FIGURE 4. A, Expression of CD117 on CD45.2+ lin- (CD3-4-8{beta}-B220-) iIEL (top panel) or iLPL (bottom panel) isolated from the gut of either control or Notch-1-deleted mixed BM chimeric mice. Numbers are mean ± SD of five (control) or eight (Notch-1 deleted) individual mice. B, Comparison of total number of CD117+ cells in CD45.2+ lin- (CD3-4-8{alpha}-) thymocytes and CD45.2+ lin- iIEL or iLPL (as described above). {square}, Control; {blacksquare}, Notch-1 deleted. Results are mean ± SD of five (control) and eight (Notch-1 deleted) individual mice.

 
Based on our data, we propose that the Notch-1 receptor mediates an essential inductive signal for T cell development in both the thymus and the intestine. Although we cannot formally exclude scenarios where Notch-1 signaling would play distinct roles in thymic and extrathymic T cell development, we favor a unified model in which a bipotential (T/B) common lymphoid precursor would migrate from the BM to the thymus or gut where ligand-receptor interaction in both tissues would lead to instruction of the precursor cells to adopt a T cell fate. In the absence of Notch-1, the instructive signal is missing and therefore precursor cells cannot develop as T cells. The reduction in relative numbers of Notch-1-/- CD117+ thymocyte precursors compared with CD117+ iIEL or iLPL precursors together with the accumulation of immature B cells of Notch-1-/- origin in the thymus but not the gut lead us to suggest that Notch-1-/- CD117+ bipotential thymic precursor cells are still able to adopt their primary fate and rapidly develop into immature B cells in the thymus. In contrast, because the gut microenvironment is apparently not permissive for ectopic B cell development (14), CD117+ Notch-1-/- precursors in the intestine are unable to adopt either a T or B cell fate and therefore persist as developmentally arrested cells.


   Acknowledgments
 
We thank Céline Maréchal for excellent technical assistance and Rose Lees for help with preparing the mixed BM chimeras.


   Footnotes
 
1 This work was supported in part by a Human Frontier Science Program Grant (to A.W.). Back

2 Address correspondence and reprint requests to Dr. H. Robson MacDonald, Ludwig Institute for Cancer Research, Lausanne Branch, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland. Back

3 Abbbreviations used in this paper: TI, thymus independent; iIEL, intestinal intraepithelial lymphocyte; iLPL, intestinal lamina propria lymphocyte; TD, thymus dependent; BM, bone marrow; lin-, lineage negative; HS, horse serum. Back

Received for publication June 30, 2000. Accepted for publication September 13, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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