© 2004 Nature Publishing Group662 | SEPTEMBER 2004 | VOLUME 4 www.nature.com/reviews/immunol

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During development, thymocytesfollow a particular migratory path-way in the thymus that allows themto interact with distinct popula-tions of stromal cells, but the pre-cise mechanisms that controlintrathymic localization and migra-tion are not well understood. Now,two studies — one focusing on themigration of early thymic immi-grants from the corticomedullaryregion to the subcapsular region,and the other focusing on themigration of positively selected thy-mocytes from the cortex to themedulla — report that signallingthrough CC-chemokine receptor 7(CCR7) is crucial for intrathymicmigration and for the maintenance ofthymic architecture.

In the first study, Misslitz andcolleagues found that CCR7 isexpressed mainly by double-negative(DN) thymocytes and by semi-mature and mature single-positive(SP) thymocytes. CCR7-deficientmice and plt/plt mice (which aredeficient in the CCR7 ligandsCCL19 and CCL21) were found tohave abnormal thymic architecture.By 6–8 weeks of age, CCR7-deficientand plt/plt mice also had reducednumbers of thymocytes but normalproportions of SP and double-positive(DP) cells. By contrast, older micehad reduced numbers of DP cells,which correlated with a severe blockin T-cell transition at early DNstages. Both types of mouse pro-duced normal T cells, althoughfewer than wild-type mice, indicat-ing that CCR7 or CCL19/CCL21deficiency can be compensated in anunknown way. Next, the authorsexamined the anatomical localiza-tion of the DN cells and found that

they accumulated at the cortico-medullary junction in older mice.Misslitz and colleagues suggest apossible explanation for the worsen-ing defect in older mice: thymocytesin young mice are derived from fetalprogenitors, which enter the imma-ture thymus when it is an unstruc-tured organ; however, after a fewweeks, progenitors enter a struc-tured organ in which signals fromCCR7 might be more crucial formigration.

In the second study, Ueno andcolleagues also studied mice defi-cient in signals from CCR7. In sup-port of their previous studies, theyobserved defective T-cell produc-tion in the neonatal period but nor-mal peripheral T-cell numbers inadult mice. Thymic architecture wasalso found to be abnormal in bothyoung and adult mice, and matureSP thymocytes accumulated in thecortex. This study shows that thedefect is worse in newborn mice,

The recognition of pathogenic bacteria byToll-like receptors (TLRs) has a crucial rolein eliciting protective innate immuneresponses. However, it is not known how TLRs can distinguish between pathogenic and commensal bacteria — which sharepathogen-associated molecular patterns such as lipopolysaccharide (LPS). In the gut, it is thought that inappropriate responses to commensal bacteria can result ininflammatory bowel diseases such as Crohn’sdisease. Now, new research published in Cell shows that TLR-mediated recognition of commensal bacteria, rather than being anunwanted side-effect, is actually important for maintaining epithelial integrity and fortissue repair.

Using oral administration of dextransulphate sodium (DSS) as a model ofintestinal injury and inflammation,Medzhitov and colleagues show that micedeficient in MyD88 — an essential adaptormolecule for TLR signalling — have increasedmorbidity and mortality after DSSadministration compared with wild-typemice. Similar results were obtained usingTLR2- or TLR4-deficient mice. Death was

associated with colonic epithelial injury,severe colonic bleeding and anaemia.

The increased epithelial injury was not dueto uncontrolled growth of commensal bacteriain the absence of restrictive TLR-dependentresponses, because commensal depletionusing antibiotics did not improve disease.Neither were there any differences in leukocyteinfiltration of the colonic epithelium betweenwild-type and MyD88-deficient mice. Instead,they found that TLR signalling throughMyD88 controls homeostasis of the intestinalepithelium. MyD88-deficient mice hadincreased basal levels of proliferation ofcolonic-crypt cells, making these cells moresusceptible to damage.As a result, intestinaltissue was unable to undergo compensatoryproliferation in response to epithelial injurycaused by γ-irradiation. These mice also haddecreased production of cytoprotective andrepair factors, such as interleukin-6 and heat-shock proteins, both before and after DSSadministration.

These results indicated a pathway by whichTLR signalling through MyD88 can protectagainst the colonic epithelial injury caused byDSS. To show that commensal bacteria trigger

this signalling pathway, the authors depletedwild-type mice of all detectable commensalbacteria using antibiotics and then treatedthem with DSS. The mice suffered severemorbidity and mortality, similar to MyD88-deficient animals. The administration ofpurified LPS or lipoteichoic acid — TLRligands expressed by Gram-negative andGram-positive bacteria, respectively —completely protected animals.

Medzhitov and colleagues therefore proposea two-step model that involves epithelialmaintenance through the constitutivedetection of commensal bacteria by TLRspresent on intestinal epithelial cells, andepithelial repair through the detection ofcommensals that breach the epithelial barrierby TLRs present on underlying fibroblastsand macrophages. Because many clinicaltreatments that are associated with intestinaldamage, such as chemotherapy, areaccompanied by antibiotic treatment toprevent opportunistic infections, thediscovery of this new pathway for thebeneficial effects of commensal bacteria has important clinical implications.

Kirsty MintonReferences and links

ORIGINAL RESEARCH PAPER Rakoff-Nahoun, S.,Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R.Recognition of commensal microflora by Toll-like receptors isrequired for intestinal homeostasis. Cell 118, 229–241 (2004).FURTHER READING Macpherson, A. J. & Harris, N. L.Interactions between commensal intestinal bacteria and theimmune system. Nature Rev. Immunol. 4, 478–485 (2004).

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