H I G H L I G H T S

Of humans, frogs, sharks and chick-ens, which is the odd one out? If youare interested in B cells, the answer ischickens — the first three animals usesomatic hypermutation to diversifythe variable (V) regions of theirrearranged antibody genes, whereaschickens, together with pigs and rab-bits, use gene conversion. Two groupshave now shown that a putative RNAediting enzyme — activation-induced cytidine deaminase (AID)— essential for somatic hypermuta-tion and immunoglobulin class-switch recombination is also requiredfor gene conversion.

It is unclear why some species usesomatic hypermutation and othersuse gene conversion. The processesare very different — somatic hyper-mutation involves the introductionof untemplated single base-pairalterations, whereas in gene conver-sion, new sequences are copied fromnearby pseudogenes. However, it hasbeen shown recently that when geneconversion is blocked in a chicken B-cell line, somatic hypermutationcan occur instead, indicating that thetwo processes might be linked mech-anistically.

The two new studies made use ofthe chicken B-cell line DT40, whichundergoes gene conversion sponta-neously. Hiroshi Arakawa and col-leagues, reporting in Science, used avariant of this cell line with aframeshift mutation in its rearrangedV segment that does not, therefore,express surface immunoglobulin(IgM). Gene conversion can repairthe mutation, leading to the expres-sion of surface IgM. The rate ofreversion provides a quick

and easy measure of gene conversion.AID was knocked out by gene target-ing to create AID−/− DT40 cells.Subclones were expanded for 18 daysthen analysed for surface IgM expres-sion. The reversion rate in AID−/− cellswas reduced by at least 100-fold, andsequencing confirmed that this wasdue to an absence of gene conversion.

Reuben Harris and colleagues alsogenerated AID−/− cells, but in an IgM+

DT40 cell line. The cells wereexpanded for 40 days, then IgMlow

cells were sorted and their V genessequenced. None of the 89 AID−/−

cells analysed had undergone geneconversion, whereas gene-conversionevents were detected in more thanone-third of the AID+/+ cells.

These studies promote AID to theposition of master controller of anti-body gene modifications. The mecha-nisms of somatic hypermutation,gene conversion and class-switchrecombination are unknown; how-ever, it has been proposed that DNAbreaks (double- or single-stranded)might be pivotal to all three processes.Harris et al. conclude by predicting,“itis likely that AID is involved in the for-mation of an initiating DNA lesioncommon to switch recombination,hypermutation and gene conversion”.

Jennifer BellReferences and links

ORIGINAL RESEARCH PAPERS Arakawa, H.,Hauschild, J. & Buerstedde, J. M. Requirement ofthe activation-induced deaminase (AID) gene forimmunoglobulin gene conversion. Science 295,1301–1306 (2002) | Harris, R. S. et al.Immunoglobulin V gene conversion in a culturedB-cell line is dependent upon AID. Curr. Biol. 2002February 11 (DOI 10.1016/S0960982202007170).

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AIDing diversity

B - C E L L R E S P O N S E S IN BRIEF

Adaptive immune response of Vγ2Vδ2+ T cells duringmycobacterial infections.Shen, Y. et al. Science 295, 2255–2258 (2002)

Correlates of protection for tuberculosis in humans remainpoorly characterized, and the role of Vγ2Vδ2+ T cells — the majorhuman γδ T-cell population — is not well documented. Shen et al.show that Vγ2Vδ2+ T cells in macaques proliferate in response toimmunization with BCG. BCG-vaccinated macaques developedprotective immunity against a fatal form of tuberculosis, whichcoincided with the expansion of alveolar Vγ2Vδ2+ T-cellpopulations. So, Vγ2Vδ2+ T cells can develop memory responsesand vaccines that target Vγ2Vδ2+ T cells might be useful.

Efficient delivery of peptides to APC by use of MHC-class-II-specific troy-bodies.Lunde, E. et al. J. Immunol. 168, 2154–2162 (2002)

Generating robust T-cell responses remains a challenge forvaccine development. Here, MHC-class-II-specific antibodieswere engineered to contain peptide epitopes from various modelantigens within their constant regions. These ‘troy-bodies’ wereshown to target the peptide to antigen-presenting cells, includingB cells, macrophages and dendritic cells. In vivo, specific T-cellactivation was 1,000–10,000-fold greater with troy-bodies thanwith native protein or peptide alone.

Attenuated experimental autoimmuneencephalomyelitis in Eta-1/ostepontin-deficient mice.Jansson, M. et al. J. Exp. Med. 168, 2096–2099 (2002)

T-helper 1 (TH1) responses have been implicated in the

pathogenesis of multiple sclerosis (MS). Jansson et al. investigatedthe role of the T

H1-promoting cytokine Eta-1 in the development

of experimental autoimmune encephalomyelitis (EAE), ananimal model of MS. Eta-1−/− and wild-type mice were equallysusceptible to the induction of EAE. However, Eta-1−/− micedeveloped less severe pathology, had diminished Th1 responsesand recovered quicker than wild-type mice.

Role for CCR7 ligands in the emigration of newlygenerated T lymphocytes from neonatal thymus.Ueno, T. et al. Immunity 16, 205–218 (2002)

The developmental stages through which T cells pass in the thymusare well defined, but it is unclear what controls the emigration ofT cells from the thymus. Previous studies have implicatedchemokine signals in this process. By adding chemokines to fetalthymic organ cultures, and analysing thymic emigration in micethat are deficient or neutralized for certain chemokines and/orchemokine receptors, the authors highlight the importance of aCCL19- and CCR7-dependent pathway of thymic emigration.

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