1、 RECEPTOR REVISION of TCR in peripheral T cells外周T細胞TCR的受體修正T cell development & TCR rearrangement T細胞發育與TCR基因重排Secondary rearrangement of TCR (receptor revision) TCR基因的二次重排(受體修正)Physiological & Clinical Significance 生理意義與臨床意義outlineI.T cell development & tcr rearrangementT細胞發育與TCR基因重排 TCR TCRV: var

2、iableJ: joiningTCR結構(D): diversityC: constantVariable regionT細胞發育 ETP （骨髓）外周T細胞庫RSS (Recombination Signal Sequences): 12-bp, 23-bp, “12/23 rule”RAG: lymphoid-specific components of the recombinaseRepair DNA double-strand breaks and modification of the ends of broken DNA strands: Ku70/80: form a ring

3、 around DNA, part of DNA-PK (DNA-dependent protein kinase)Artemis: nuclease activityDNA ligase IV: join DNA ends TdT (Terminal Deoxynucleotidyl Transferase)TCR基因重排與受體庫的建立1. Endonucleolytic cleavage: RAGs, RSS 2. Signal joint formation: DNA ligase IV3.Coding joint formation: Ku70/80TCR基因重排與受體庫的建立3.Co

4、ding joint formation:Ku70/80, DNA-PKcs, ArtemisDNA repair enzymes, TdTDNA ligase IVDiversity of TCR repertoire:Combinatonial diversityJunctional diversityCombination of chainsTCR基因重排與受體庫的建立II.Secondary rearrangement of TCR (receptor revision)TCR基因的二次重排(受體修正)外周T細胞的分化發育H. David, Jr. Wagner, Re-shaping

5、 the T cell repertoire: TCR editing and TCR revision for good and for bad, Clinical Immunology 2007; 123: 1-6Receptor revision: a process in which peripheral T cells rearrange their TCR gene and alter TCR expressionCommon processRecorded cases:CD4+ T cells from V5 transgenic miceDiabetogenic CD4+ T

6、cells from NOD mice (non-obese diabetic mice)CD8+ T cells from normal human donorsCD4+ T cells from ataxia-telangiectasia patients (AT, 失調性毛細血管擴張癥, defective DNA repair response)Detective indexes: Membranous TCR segmentsRAG expression at different levels (mRNA, protein)Recombination intermediates (s

7、ignal joint)T細胞受體修正C.J. McMahan, P.J. Fink, RAG reexpression and DNA recombination at T cell receptor loci in peripheral CD4+ T cells, Immunity 1998; 9:637-47J. Scott Hale, Pamela J. Fink, T-cell receptor: friend or foe? Immunology 2010; 129: 467-73受體修正的過程Signals(Stimuli + Microenvironment)Cellular

8、ResponsePhysiological ResultsSignalsAutoantigen: islet-specific CD8+ T cells (mice) cell autoantigen + local inflammatory environment in PLN (胰腺淋巴結)Superantigen: CD4+ T cells from V5 Tg miceMtv-8 + germinal center environment (B cell dependent)受體修正的過程 S. Pau et al., RAG-dependent peripheral T cell r

9、eceptor diversification in CD8+ T lymphocytes, Proc Natl Acad Sci 2002; 99(24): 15566-71 J. Scott Hale, Pamela J. Fink, T-cell receptor: friend or foe? Immunology 2010; 129: 467-73(V5)Cellular responseIn V5 Tg miceA 3-step processThe process is well-regulatedSignificance of this finding受體修正的過程Revisi

10、ngPost-revisionExitingT cell-B cell boundaryTfh phenotype(+) Bcl-6B cell follicleTh17 phenotype but act as Tm(+) Bcl-6, SAP; (-) Blimp-1Other tissuesTm phenotype(+) SAP Kalynn B. Simmons et al., Modulation of TCR surface expression during TCR revision, Cellular Immunology 2012; 272(2): 124-9 Lauren

11、E. Higdon et al., Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions, Proc Natl Acad Sci 2014; 111(15): 5652-7III.physiological & Clinical Significance生理意義與臨床意義Enrich the receptor repertoire (受體庫)Might be a double-edged sword conside

12、ring immune tolerance Maintain peripheral T cell toleranceSelf-superantigen / self-antigen induced TCR revision Potential to induce autoimmunitySelection pressure out of thymusDual TCRs生理意義P. Serra et al., RAG-dependent peripheral T cell receptor diversification in CD8+ T lymphocytes, Proc Natl Acad

13、 Sci 2002; 99(24): 15566-71Upregulated level of RAGs in autoimmune patients peripheryExplain the reason for maintenance of immune diseaseSignal: CD40 (interact with CD154)T cell type: Th40Inhibition factor: Fas (autoimmune microenvironment)May contribute to the predispositon of AT patients with ATM-

14、mutated protein to develop mature-type T lymphoma臨床意義 Gisela M. Vaitaitis, David H. Wagner, CD40 interacts directly with RAG1 and RAG2 in autoaggressive T cells and Fas prevents CD40-induced RAG exression, Cellular & Molecular Immunology 2013; 10: 483-9 E. Lantelme et al., Increased frequency of RAG

15、-expressing, CD4+CD3low peripheral T lymphocytes in patients with defective responses to DNA damage, Eur. j. Immunol. 2000; 30: 1520-5Any other signals leading to TCR revision?Is the enzymic process of rearrangement identical to that in the thymus?Is it a protective process or a danger-generating pr

16、ocess?展望Charles A. Janeway Jr. et al., JANEWAYS IMMUNOBIOLOGY (8th edition), USA: Garland Science, 2012H. David, Jr. Wagner, Re-shaping the T cell repertoire: TCR editing and TCR revision for good and for bad, Clinical Immunology 2007; 123: 1-6J. Scott Hale, Pamela J. Fink, T-cell receptor: friend o

17、r foe? Immunology 2010; 129: 467-73S. Pau et al., RAG-dependent peripheral T cell receptor diversification in CD8+ T lymphocytes, Proc Natl Acad Sci 2002; 99(24): 15566-71Kalynn B. Simmons et al., Modulation of TCR surface expression during TCR revision, Cellular Immunology 2012; 272(2): 124-9Lauren

18、 E. Higdon et al., Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions, Proc Natl Acad Sci 2014; 111(15): 5652-7P. Serra et al., RAG-dependent peripheral T cell receptor diversification in CD8+ T lymphocytes, Proc Natl Acad Sci 2002; 99(24): 15566-71Gisela M. Vaitaitis, David H. Wagner, CD40 interacts directly with RAG1 and RAG2 in autoaggressive T cells and Fas prevents CD40-induced RAG exression, Ce