(Antigen presentation to T lymphocytes) · 2015-06-29 · (Antigen presentation to T lymphocytes) 2014년도2학기약품면역학제5강(2/43) ... Peptide loading by HLA -DM •

2014년도 2학기약품면역학제 5강 (1/43)

Chapter 5

T 림프구에 대한 항원제시

(Antigen presentation to T lymphocytes)


적응면역반응(adaptive immune response)

• 주조직적합복합체(major histocompatibility complex, MHC)

• 항원처리(antigen processing)

• 항원제시(antigen presentation)


MHC class I vs MHC class II


막으로구분되는 2개의구획

• 세포질내(cytosolic compartment)

• 소포내(vesicular compartment)


세포內 세포外

세포질내 vs 소포내병원체


세포內항원의처리및제시

• 항원처리연관운반체 1, 2(transporters associated with antigen processing-1, and 2, TAP1 and TAP2)

• MHC class I분자에결합하는펩티드를세포질에서형질내세망(ER)으로능동적으로운반


Ubiquitin-dependent degradation pathway


프로테아좀(proteasome)

• Multi-catalytic protease complex• 7개의소단위(subunit)를가진고리• 4층구조, 28개의소단위큰원통형복합체(cylindrical

complex)


Cross-presentation by MHC I

• 교차제시(cross-presentation)– MHC class I 분자에의한 CD8 T 세포에외인성항원제시

• Retrograde translocation (retro-translocation) from ER to cytosol

• Transport from cytosol back to ER by TAP


MHC class I의항원처리및제시

• MHC class I– α chain and β2 microglobulin

• MHC class I molecules are retained in the ER until they bind a peptide

• Peptide loading complex– Calnexin (chaperone) + MHC I α– Calreticulin (chaperone) + MHC I α + β2m– Erp57 (chaperone) + MHC I α + β2m

• Thiol oxidoreductase– Tapasin

• TAP-associated protein– TAP transporter


Animation demoPeptide editingPeptide loading complex

MHC class I의항원처리및제시• DRiPs – defective ribosomal products


면역회피물질(immunoevasins)

• 다수의바이러스가만들어냄• Viral evasin

• HCMV (human cytomegalovirus) US6• Herpes simplex virus ICP47

– Inhibit TAP-mediated transport

• Adenovirus E19– Inhibit Tapasin and TAP interaction

• CMV US11– MHC class I의전위(dislocation)

Animation demo


MHC class II의항원처리및제시

• Receptor-mediated endocytosis• 엔도솜(endosome)• 산도가높아짐(acidified endocytic vesicles)• Lysosome과합쳐짐

• 산성단백질분해효소- Cystein protease, cathepsin B, D, S, and L

• IFN-γ-induced lysosomal thiol reductase (GILT)– Reduce disulfide bonds

• 낮은 pH에서활성화됨• 소포내의단백항원을분해




• 불변사슬 Ii(invariant chain, Ii)• CLIP (class II-associated invariant-chain peptide)• ER에서다른펩티드가MHC class II에붙는것을방지• MIIC (MHC class II compartment)

산성화엔도좀



HLA-DM

• MHC class II 유사분자• α and β chains• MHC class II 분자와불안정하게결합한펩티드혹은 clip을제거하고안정하게결합한펩티드를적재하는촉매역할

• 펩티드편집(peptide editing)• TAP 분자가MHC class I 분자에펩티드결합을용이하게하는것과유사


Animation demo

Peptide loading by HLA-DM

• HLA-DO – negative regulator of HLA-DM


MHC and its functions

• Polygeny (다양성, 다유전자성)– 200개이상의유전자

• Polymorphism (다형성)– 각유전자의변이형(variants) 존재

• MHC class I and II genes• Human leukocyte antigen (HLA, 사람백혈구항원) genes• H-2 genes from mouse

• MHC class II transactivator (CIITA) -> IFN-γ -> MHC 관련유전자유도


MHC polymorphism and polygeny

이형접합성(heterozygous)

공동우성(co-dominant)


Different alleles of an MHC class I

• Allelic variation(대립유전자의변이) occurs at specific sites within MHC molecules

• Different alleles of an MHC I bind different peptide


제한인식(restricted recognition)(制限認識, restricted recognition)

• MHC restriction• T 세포수용체의특이성

• 수용체가인식하는펩티드와수용체에결합된MHC 분자모두에의해특징지어짐

• T 세포수용체는펩티드와 MHC 분자를동시에인식

• Alloreaction or alloreactivity (동종반응)– Alloreactive T cells recognize non-self or foreign MHC molecules


제한인식(restricted recognition)


슈퍼항원(super antigen)

• 포도알균장독소(staphylococcal enterotoxin, SE)• 독성쇽증후군독소-1(toxic shock syndrome toxin-1, TSST-1)

• T세포와MHC에직접결합• No antigen specificity• 2-20%의 T 세포를자극할수있음• 보통은만개의 T 세포중하나만을자극)• Overproduction of IL-2• Fever, nausea, vomiting, diarrhea and shock


animation demo

슈퍼항원(Super antigen)


Chapter 6

면역계 수용체를 통한 신호전달 1(signaling through immune system

receptors)


세포내신호전달경로

• 신호전달(signal transduction)

• 효소-결합수용체 (enzyme-linked receptors)

• 단백인산화효소(protein kinase)– Tyrosine kinase– Serine/threonine kinase– 단백인산화(protein phosphorylation)

• 단백인산분해효소(protein phosphatase)

• Large multiprotein signaling complex


단백인산효소를통한신호전달


단백인산효소를통한신호전달


단백 상호 작용 도메인


• 골격단백(scaffold protein)• SH2 (Src homology 2) domain + pYXXZ motif

골격단백


• 매개단백(adaptor protein)- Grb2• 신호전달단백(signaling protein) - SOS• SH3 domain + PXXP motif

매개단백


신호전달과정은시작신호를증폭시킴

kinase cascade Second messengers


작은 G 단백(small G protein)

• 작은 GTPase(small GTPase)– GTP를가수분해

• GTP 결합단백(GTP-binding protein)• Ras 계(Ras family) – Ras, Rac, Rho, Cdc42

• 구아닌뉴클레오타이드교환인자(guanine nucleotide exchange factor, GEF) – turn-on

• GTPase 활성단백(GTPase-activating protein, GAP) – turn-off


Small G protein의활성화

GAP

Turn-on Turn-off

G P P

P P

PP P P P

G

G G


Phosphatidyl inositol (PI)

• 세포막지질 2차전령물질

• 인산화이노시톨인산화효소(phosphatidylinositol kinase)

• Two fatty acids + glycerol + inositol ring


PP

Phosphatidyl inositol (PI) Phosphatidyl inositol4,5 bisphosphate (PIP2)

PI kinase



PP

Phosphatidyl inositol4,5 bisphosphate (PIP2)

Phospholipase C (PLC)

P P

Diacylglycerol (DAG)

Inositol triphosphates (IP3)

HH



신호전달단백의세포막집합


지질뗏목(lipid raft)

• 콜레스테롤과스핑고리피트와같은특정지질이풍부

• 당지질풍부미세도메인(glycolipid-enriched microdomains, GEMs)

• 세제불용성당지질풍부도메인(detergent-insoluble glycolipid-rich domain, DIG)

• GPI (glycosyl phosphatidyl inositol) link


Animation demo

지질뗏목(lipid raft)


Signal turn-off by ubiqutination

• Ubiquitin conjugation to lysine resides of target protein• Ubiquitin ligase


B 세포수용체복합체(BCR complex)

• B cell receptor complex

• 불변부속단백(invariant protein) Igα and Igβ

• 세포표면면역글로불린(cell surface immunoglobulin)

• 면역수용체티로신기반활성화모티프(immunoreceptor tyrosine-based activation motif, ITAM)


T 세포수용체복합체(TCR complex)

• T cell receptor complex

• CD3– 2개의 CD3ε, 1개의 CD3δ, 1개의

CD3γ, 2개의 CD3ζ (zeta)

• 10개의 ITAM

Documents

(Antigen presentation to T lymphocytes) · 2015-06-29 · (Antigen presentation to T lymphocytes) 2014년도2학기약품면역학제5강(2/43) ... Peptide loading by HLA -DM •