Abstract
The adaptive immune response in vertebrates depends on the expression of antigen-specific receptors in lymphocytes. T-cell receptor (TCR) gene expression is exquisitely regulated during thymocyte development to drive the generation of αβ and γδ T lymphocytes. The TCRα, TCRβ, TCRγ, and TCRδ genes exist in two different configurations, unrearranged and rearranged. A correctly rearranged configuration is required for expression of a functional TCR chain. TCRs can take the form of one of three possible heterodimers, pre-TCR, TCRαβ, or TCRγδ which drive thymocyte maturation into αβ or γδ T lymphocytes. To pass from an unrearranged to a rearranged configuration, global and local three dimensional (3D) chromatin changes must occur during thymocyte development to regulate gene segment accessibility for V(D)J recombination. During this process, enhancers play a critical role by modifying the chromatin conformation and triggering noncoding germline transcription that promotes the recruitment of the recombination machinery. The different signaling that thymocytes receive during their development controls enhancer activity. Here, we summarize the dynamics of long-distance interactions established through chromatin regulatory elements that drive transcription and V(D)J recombination and how different signaling pathways are orchestrated to regulate the activity of enhancers to precisely control TCR gene expression during T-cell maturation.
Highlights
The adaptive immune response in vertebrates depends on the expression of antigen-specific receptors in lymphocytes
Notch-dependent recruitment of RUNX1 and MYB is crucial for Eγ and Eδ activity during thymocyte development and, for TCRγ and TCRδ gene expression
To the parallel regulation of Eδ and Eγ by Notch signaling, it is possible that IL-7R might play a similar role in Eδ function and TCRδ gene expression as it does for the regulation of the Eγ and TCRγ genes
Summary
T lymphocytes acquire the ability to recognize foreign antigens, providing protection against diverse pathogens. Two different types of T lymphocytes can be distinguished based on TCR expression: the vast majority of T lymphocytes (more than 90% in humans and mice) are called αβ T cells because they express a TCRαβ composed of TCRα and TCRβ chains, whereas the remaining T lymphocytes are called γδ T cells because they express a TCRγδ composed of TCRγ and TCRδ chains. These receptors consist of a variable and a constant (C) region. Itthise swuirdvievlayl oafcocnelpyt3e–d5%thoaftDαPβth/γymδ olicnyeteasg, we hfaicthethdeenpdeinffdersenotniattehientsotSrePnthgythmoocfytseisgannadlimngigrtaoteDN3a thymotcoytthees:ptehriypmheorycyatseαsβthTaltyrmepcehiovceytleosw. levels of signaling through the pre-TCR during β-selection develop intIot iαsβwTidceelyllsa,cwcehpeterdeatshtaht oαsβe/γthδaltinrecaegievfeastetrdonepgesnidgsnaolns thherosutrgehngtthheoTfCsRigγnδaldinegvetoloDpNin3tao γδ T cells [1t2h]y. mInoctyhtiessc: othnytmexotc,yNteosttchhatsirgenceailvienglocwonletvreiblsuotfessitgonathliengdtehtreorumgihntahteiopnreo-fTαCβR/dγuδrfinagteβb-syelmecotidounlating the intdenevseitlyopoifntthoeαβsiTgncealllss,rwecheeirveeads tdhousreinthgatthreycmeivoecysttreondgevsieglnoaplsmthernotu[g1h0]th. eHToCwReγvδedre, voeploppoisnittoe γoδutputs are cell opbroTmosepgorcpedveonlueslislidtatoet[i1rinnos2gu]p.httprIuhnouemtmstihanoaintrsteesencsosaoibαnntystβdeeroxTvmtf,etcdiNhceeeiolnl:tscdhiehgiuxnffmsoaeigglarsneneanrnselotiacniuenagidstviecosmodntnri,codterwun:ibrgehiuxnetNogergseoteahttnsocyohmiutthsospecisgrytdorntoeemanteldgoirenmtNvegeisonliotaγncpthδimomsTneiugnconrtefialn[ll1αien0dβ]g/u.iγffinHδnecoromfewamntueetrvmiiebanriyte,titoendiTn humanuncceollmsm[1it0t]e.dTThceecllopnrtorgoevneitrosrisalparonmdosteesemαβinTglcyelol pdipffoesreitnetiraotiloens, owfheexroeagseintopurosmNootetschγδsiTgnceallling in the devdeiflfoepremnteianttioonf iαnβhaunmdanγδceTllsly[m10p].hTohceytceosntirnovheurmsiaalnasnadnsdeemmiicneglaypoppepaorstiotebreolaesconf seexqougeennocuesof the cell staNgoetacht wsighniaclhintghiensethseigdnevaellsoaprmeernetcoefivαeβdanind eγaδcThlcyamspeh[o1c0y]t.eIsninahdudmitaionns atnodNmoitccehapapnedarTtCo Rbesaignals, signalicnognsmeqeudeiantceedofbtyhethceellinsttaegreleaut kwihnic7hrtehceespetsoigrn(aILls-a7rRe)r,ewcehivicehd idneecaacyhscdasuer[i1n0g].tIhneadtrdaintisointitoonNforotcmh DN4 to DP tahnydmToCcRystiegsn(aFlsi,gsuigrena2l)in, gismesesdeiantteidalbfyotrhceeilnltseurlrevuikvinal7arnedcemptoartu(IrLa-t7iRon), w[1h9i]c.h decays during the transition from DN4 to DP thymocytes (Figure 2), is essential for cell survival and maturation [19]
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