CD8+T細胞在自體免疫疾病中之角色

(1)

402 110 10

CD8+T

CD8+T /

CD8+T

CD8+T -MHC

;

/ CD8+T

CD8+T

( Autoimmune diseases )

CD8+T ( Autoreactive CD8+T cells ) Fas ( Fas-mediated killing pathway )

/ ( Perforin / Granzyme-mediated

killing pathway ) ( Cytokines ) ( Chemokines )

( non-self ) ( )

( altered-self ) ( )

( )

(2)

CD8+T

T

CD8+ T

( ) CD8+T ( activation ) ( ) CD8+T

( effector ) ( )

CD8+T ( cytokines )

( chemokines ) ( ) CD8+T

( negative regulation )

CD8+T

CD8+T -MHC-class I

T ( Tc cytotoxic T lymphocytes; CTL ) CTL

CD8+T

/ Fas

CD8+T

CD8+T CD8+T CD8+T

(IFN)

Th2 IL-10

( Heymann

(IBD) (MS)

IFN- - CD8+T

Fas

/ Fas

(Vogt-Koyanagi-Harada syndrome)

(61) Ulrich Walter & Pere Santamaria. (2005) Curr Opin Immunol 17: 624-31.

(3)

CD8+ T

( )

( Type 1 diabetes; T1D ) ( non-obese di- abetic; NOD ) T1D

CD4+T

CD8+T

¹

( dendritic cells; DCs )

CD8+T

( productive ) ( )

( non-productive ) ( )

D C s

( )

D C s

-MHC

²

T ( TCR ) -MHC

3-4

4 3

T -DCs

T ( T cell re-

ceptor; TCR ) cbl-b

T

³

( toll-like

receptor; TLR ) ( Ligands ) DCs /

T

5-7

C p G D N A

Hsp70 ( ) DCs

T

5-7

CD8+T MHC

CD8+T

CD4+T helper CD154

CD40 CD4+T helper

DCs CD8+T

D C s

8

( T helper

D C s )

CD4+CD25+T T

⁷

D C s DCs

C D 8 + T -MHC

9

T C R CD8+T

10

- 6 - 206-214 ( islet- specific glucose-6-phosphatase catalytic subunit-re- lated protein; IGRP

^206-214

)

¹¹

C D 8 + T 1 5 - 25%

¹²

NOD

IGRP206-214 CD8+T

13 12

( ) T

( )

T

14

CD8+T

NOD

T

1 4

( APCs )

15-16

CD8+T

IGRP

^206-214

IGRP

^206-214

- CD8+T

4

(4)

I G R P C D 8 + T ( I G R P epitope -specific CD8+T cells )

4

CD8+T

( target cell ) ( ) -

MHC Fas ( Fas

ligand; FasL )

Fas ( Fas TNF-R

Fas ( FasL )

Fas ) ( ) CD8+T

( perforin ) ( granzymes )

( serine proteases )

( ) CD8+T

TNF- IFN-

1,17

NOD

Fas ( Fas-associated death domain; FADD )

FasL

18

N O D

^{1 9}

NOD CD8+T

Fas

( perforin-mediated ) T ( T-cell avidity )

Fas T

20

CD8+T

NOD

T NOD

MHC

T ( cytotoxic T lymphocyte ; CTL )

CD8+T

2 1

2- NOD

( phenotype )

²²

T

C D 8 + T T

T NOD

-1 ( retinoic acid early inducible-1;

R A E - 1 ) R A E - 1 N K G 2 D

NKG2D ( a receptor on NK cells and T cells, is a type II membrane glyco-protein that is expressed on the cell surface of essentially all NK cells, gd-TcR+ T cells, and CD8+ T cells )

CD8+T

IGRP

^206-214

NOD NKG2D

( m A b ) I G R P

2 0 6 - 2 1 4

CD8+T

23

T NKG2D

T

²⁴

( SLE )

D C s ( IFN- ) IFN-

D C s

CD4+T

^25-26

CD8+T

( ) SLE

T SLE SLE

CD8+T

(5)

IFN- DCs T Fas

( nucleosomal Ag )

²⁷

S L E CD8+T

Mer (

) DNA

DNA SLE

28

SLE I IFN

CD8+T

29

CD8+T ( multiple sclerosis; MS )

MS ( C-

NS ) MS

CD4+T

CNS ( myelin-

specific ) CD8+T ( transfer )

³⁰

MS CD8+T

3 1

CD8+T

32

MS

( experimental autoimmune encephalomyelitis; EAE )

CD8+T

³³

( regulatory ) CD8+T CNS

C D 8 + T

MS CD8+T

IFN- IL-10

³⁴

CD8+T

CD8+T ( T N F - )

( IFN- ) IL-1

- 3

( suppressor of cytokine signaling-3; SOCS-3 )

IL-1 IFN-

³⁵

N-

OD IL-1 ( IL-1R )

IL-1R

( inducible nitric oxide synthase;

iNOS ) TNF- IFN-

36

( NO

) TNF- IFN- D C s T N F 1

( upregulation ) Fas M H C

1

SOCS-1 Fas MHC

I NOD

37

MHC I

( TLR ) MHC

I

38

TNF-

EAE/MS ( inflammatory bowel

disease; IBD ) ( experimental

myasthenia gravis; EMG ) ( rheumatoid arthritis; RA )

39

T ( CTL )

I F N -

MHC I

⁴⁰

TNF-

R A T N F -

SLE TNF-

( IFN- ) ( downregulation )

41

( chemokines )

C CC CXC

C X 3 C CD8+T

CXCL10/IP10 ( CXC chemokine ligand 10 /

(6)

Interferon- -inducible protein 10 )

CD8+T ( recruit-

ing )

42

CD8+T

CNS CCL5 ( chemokine ligand 5 )

43

CD8+T

( ectopic germinal centers ) CD8+T

44

CD8+T

( ) Qa-1 T ( regulatory T

cells; Tr ) C D 8 + T

( EAE )

MHC Ib Qa-1

CD8+T

^45-47

T

CD4+ T Qa-1-

- ( Qa-1-self-peptide complexes )

48

EAE

( myelin basic protein; MBP )

C D 4 + T

^{4 9}

Qa-1- - T

CD8+T

50

C D 4 + T

^{4 6 , 5 1}

Qa-1 CD8+T

T

Qa-1 CD8+T

52- 53

( ) CD8+CD28 T

C D 8 + C D 2 8 C D 8 +

EAE RA

^54-55

Qa-1 T

( CD4+CD25+T T

( nature killer T cell; NKT ) )

CD8+CD28 T

3 ( inhibitor Immunoglobulin-like transcript 3; ILT3 ) 4 ( ILT4 )

( APCs )

54,56

( ) gp180/CD1d T

gp180

MHC I CD1d

CD8+T

T ( IBD )

Tr

⁵⁷

( ) 4-1BB T

4-1BB ( TNF recep-

tor family ) T

T

4-1BB

CD8+T

DCs CD11c

IFN- DCs

2 , 3 - ( i n d o l e a m i n e 2 , 3

dioxygenase; IDO ) T

⁵⁸

4-

1 B B m A b T

( TLR ) ( TGF )

59

4-1BB

C D 4 + T

60

C D 8 + T

CD8+T

T

(7)

CD8+T

MHC T

61

CD8+T

MHC T

CD8+T

1.Santamaria P. Effector lymphocytes in islet cell autoimmunity.

Rev Endocr Metab Disord 2003; 4: 271-80.

2.Kruts C, Sutherland M, Davery G, et al.CD8T cell ignorance or tolerance to islet antigens depends on antigen dose. Proc Natl Acad Sci USA 1999; 96: 12703-7.

3.Gronski MA, Boulter JM, Moskophidis D, et al.TCR affinity and negative regulation limit autoimmunity. Nat Med 2004; 10:

1234-9.

4.Han B, Serra P, Amrani A, et al.Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low-affinity peptide. Nat Med 2005; 11: 645-52.

5.Shi Y, Evans JE, Rock KL. Molecular identification of danger signal that alerts the immune system to dying cells. Nature 2003;

425: 516-21.

6.Millar DG, Garza KM, et al. Hsp70 promotes antigen-present- ing cell function and converts T-cell tolerance to autoimmunity in vivo. Nat Med 2003; 9: 1469-76.

7.Serra P, Amrani A, Yamanouchi J, et al. CD40 ligation relea- ses immature dendritic cells from the control of regulatory CD4+CD25+T cells. Immunity 2003; 19: 877-89.

8.Hernandez J, Aung S, Marquardt K, et al. Uncoupling of proli- ferative potential and gain of effector function by CD8 ( + ) T cells responding to self-antigens. J Exp Med 2002; 196: 323-33.

9.Savinov AY, Wong FS, et al. Presentation of antigen by en-

dothelial cells and chemoattraction are required for homing of insulin-specific CD8+T cells. J Exp Med 2003; 197: 643-56.

10.Santamaria P. Kinetic evolution of a diabetogenic CD8+ T cell response. Ann N Y Acad Sci 2003; 1005: 88-97.

11.Lieberman SM, Evans A, Han B, et al. Identification of the be- ta cell antigen targeted by prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci USA 2003; 100: 8384-8.

12.Amrani A, Verdaguer J, Serra P. Progression of autoimmune diabetes driven by avidity maturation of a T-cell population.

Nature 2000; 406: 739-42.

13.Trudeau JD, Kelly-Smith C, Verchere CB, et al. Prediction of spontaneous autoimmune diabetes in NOD mice by quantifica- tion of autoreactive T cells in peripheral blood. J Clin Invest 2003; 111: 217-23.

14.Han B, Serra P, Yamanouchi J, et al. Developmental control of CD8 ( + ) T cell-avidity maturation in autoimmune diabetes. J Clin Invest 2005; 115: 1879-87.

15.Kedl RM, Rees WA, Hildeman DA, et al. Marrack p. T cells compete for access to antigen-bearing antigen -presenting cells.

J Exp Med 2000; 192: 1105-13.

16.Kedl RM, Schaefer BC, Kappler JW al. T cells downmodulate peptide- MHC complexes on APCs in vivo. Nat Immunol 2002;

3: 27-32.

17.Kim S, Kim K, Hwang D. Inhibition of autoimmune diabetes by Fas ligand: the paradox is solved. J Immunol 2000; 164: 2931- 6.

18.Allison J, Thomas HE, Catterall T, Kay TWasser A. Transgenic Expression of Dominant- Negative Fas-Associated Death Domain Protein in Cells Protects against Fas Ligand-Induced Apoptosis and re duces Spontaneous Diabetes in Nonobese Diabetic Mice. J Immunol 2005; 175: 293-301.

19.Odermatt B, Seiler P. Reduced incidence and delayed onset of diabetes in perforin-deficient non- obese diabetic mice. J Exp Med 1997; 186: 989-97.

20.Qin H, Trudeau JD, Reid GS, et al. Progression of spontaneous autoimmune diabetes is associated with a switch in the killing mechanism used by autoreactive CTL. Int Immunol 2004; 16:

1657-62.

21.Yamanouchi J, Verdaguer J, Han B, et al. Cross-priming of dia- betogenic T cells dissociated from CTL-induced shedding of be- ta cell autoantigens. J Immunol 2003; 171: 6900-9.

22.Hamilton-Williams EE, Palmer SE, Charlton B.M. Beta cell MHC class I is a late requirement for diabetes. Proc Natl Acad Sci USA 2003; 100: 6688-93.

23.Ogasawara K, Hamerman J, Ehrich L, et al. NKGD2 blockade prevents autoimmune diabetes in NOD mice. Immunity 2004;

20: 757-67.

24.Groh V, Bruhl A, El-Gabalawy H, Nelson J. Stimulation of T cell autoreactivity by anomalous expression of NKGD2 and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci USA 2003; 100: 9452-7.

25.Blanco P, Palucka A, Gill M, Pacual V, Banchereau J. Induction

(8)

of Dendritic Cell Differentiation by IFN- in Systemic Lupus Erythematosus. Sci. 2001; 294: 1540-3.

26.Baechler EC, Gregersen PK, Behrens TW. The emerging role of interferon in human systemic lupus erythematosus. Curr Opin Immunol 2004; 16: 801-7.

27.Blanco P, Pitard V, Viallard JF,et al. Increase in activated CD8+

T lymphocytes expressing perforin and granzyme B correlates with disease activity in patients with systemic lupus erythe- matosus. Arthritis Rheum 2005; 52: 201-11.

28.Scott R, McMahon E, Pop S, et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 2001; 411: 207- 11.

29.Santiago-Raber ML, Baccala R, Haraldsson KMl. Type-1 inter- feron receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med 2003; 197: 777-88.

30.Huseby ES, Liggitt D, Brabb T. A pathogenic role for myelin- specific CD8 ( + ) T cells in a model for multiple sclerosis. J Exp Med 2001; 194: 669-76.

31.Babbe H, Roers A, Waisman A, et al. Clonal expansions of CD8 ( + ) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 2000; 192: 393-404.

32.Skulina C, Schmidt S, Dornmair K, et al. Multiple sclerosis:

brain-infiltrating CD8+ T cells persist as clonal expansion in the cerebrospinal fluid and blood. Proc Natl Acad Sci USA 2004;

101: 2428- 33.

33.Perchellet A, Stromnes I, Pang JM, Goverman J. CD8+ T cells maintain tolerance to myelin basic protein by epitope theft . Nat Immunol 2004; 5: 606-14.

34.Crawford MP, Yan SX, Ortega SB, et al. High prevalence of au- toreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay. Blood 2004;

103: 4222-31.

35.Karlsen AE, Ronn SG, Lindberg K, et al. Suppressor of cytokine signaling 3 ( SOCS-3 ) protects beta-cells against interleukin-1 and interferon-gamma-mediated toxicity. Proc Natl Acad Sci USA 2001; 98: 191-6.

36.Thomas HE, Irawaty W, Darwiche R, et al. IL-1 receptor defi- ciency slows progression to diabetes in the NOD mouse.

Diabetes 2004; 53: 113-21.

37.Chong MM, Chen Y, Darwiche R, et al. Suppressor of cytokine signaling-1 overexpression protects pancreatic beta cells form CD8+ T cell-mediated autoimmune destruction. J Immunol 2004; 172: 5714-21.

38.Lang KS, Recher M, Junt T, et al. Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune diseases.

Nat Med 2005; 11: 138-45.

39.Santamaria P. Effector lymphocytes in autoimmunity. Curr Opin Immunol 2001; 13: 663-9.

40.Cohen ES, Bodmer HC. Cytotoxic T lymphocytes recognize and lyse chondrocytes under inflammatory, but not non- inflammatory conditions. Immunology 2003; 109: 8-14.

41.Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J.

Cross-regulation of TNF and IFN- alpha in autoimmune di- seases. Proc Natl Acad Sci USA 2005; 102: 3372-7.

42.Ejrnaes M, Videbaek N, Christen U, et al. Different diabetogenic potential of autoaggressive CD8+ clonnes associated with IFN- gamma-inducible protein 10 ( CXC chemokine ligand 10 ) pro- duction but not cytokine expression, cytolytic activity, or hom- ing characteristics. J Immunol 2005; 174: 2746-55.

43.Matejuk A, Dwyer J, Ito A, et al. Effects of cytokine deficiency on chemokine expression in CNS of mice with EAE. J Neurosci Res 2002; 67: 680-8.

44.Kang YM, Zhang X, Wagner UG, et al. CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid syn- ovitis. J Exp Med 2002; 195: 1325-36.

45.Jiang H, Ware R, Stall A, et al. Murine CD8+ T cells that speci- fically delete autologous CD4+ T cells expressing V beta 8 TCR:

a role of the Qa-1 molecule. Immunity 1995; 2: 185-94.

46.Jiang H, Kashleva H, Xu LX, et al. T cell vaccination induces T cell receptor V -specific Qa-1- restricted regulatory CD8+ T cells. Proc Natl Acad Sci USA 1998; 95: 4533-7.

47.Hu D, Ikizawa K, Lu L. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol 2004; 5: 516-23.

48.Sarantopoulos S, Lu L, Cantor H. Qa-1 restriction of CD8+ sup- pressor T cells. J Clin Invest 2004; 114: 1218-21.

49.Jiang H, Curran S, Ruiz-Vazquez E. Regulatory CD8+T cells fine-tune the myelin basic protein- reactive T cell receptor V beta repertoire during experimental autoimmune en- cephalomyelitis. Proc Natl Acad Sci USA 2003; 100: 8378-83.

50.Panotsakopoulou V, Huster KM, McCarty N. Suppression of au- toimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes. J Clin Invest 2004; 113: 1218- 24.

51.Sullivan BA, Kraj P, Weber DA, Ignatowicz L, Jensen PE.

Positive selection of a Qa-1-restricted T cell receptor with speci- ficity for insulin. Immunity 2002; 17: 95-105.

52.Jiang H, Wu Y, Liang B. An affinity/avidity model of peripher- al T cell regulation. J Clin Invest 2005; 115: 302-12.

53.Lo WF, Woods AS, DeCloux A, et al. Molecular mimicry me- diated by MHC class Ib molecules after infection with gram negative pathogens. Nat Med 2000; 6: 215-8.

54.Najaflan N, Chitnis T, Salama AD, et al. Regulatory functions of CD8+CD28- T cells in an autoim- mune disease model. J Clin Invest 2003; 112: 1037-48.

55.Davila E, Kang YM, Park YW, et al. Cell-based Immunotherapy with Suppressor CD8+ T Cells in Rheumatoid Arthritis. J Immunol 2005; 174: 7292-301.

56.Chang CC, Ciubotariu R, Manavalan JS. Tolerization of den- dritic cells by T ( S ) cells: the crucial role of inhibitory recep- tors ILT3 and ILT4. Nat Immunol 2002; 3: 237-43.

57.Brimnes J, Allez M, Dotan I, Shao L, Nakazawa A, Mayer L.

Defects in CD8+ regulatory T cells in the lamina propria of pa- tients with inflammatory bowel disease. J Immunol 2005; 174:

5814-22.

58.Seo SK, Choi JH, Kim YH, et al. 4-IBB-mediated immunothe-

(9)

rapy of rheumatoid arthritis. Nat Med 2004; 10: 1088-94.

59.Myers L, Takahashi C, Mittler RS, Rossi RJ, Vella AT. Effector CD8 T cells possess suppressor function after 4-1BB and Toll- like receptor triggering. Proc Natl Acad Sci USA 2003; 100:

5348- 53.

60.Lee SW, Vella AT, Kwon BS, Croft M. Enhanced CD4 T cell Responsiveness in the Absence of 4-1BB. J Immunol 2005; 174:

6803-8.

61.Ulrich Walter, Pere Santamaria. CD8+T cells in Autoimmunity.

Current Opinion Immunol 2005; 17: 624-31.

The Investigation of the Specific Roles of CD8+T Cells in Different Autoimmune Diseases

Pei-Lun Chou, Men-Chi Chen

²

, and Gregory J Tsay

^1,2

Many evidences showed that CD8+T cells contribute to the initiation, progression and regulation of seve- ral pathogenic autoimmune responses in which these cells were not previously thought to play a major role. CD8+T cells can kill target cells directly, by recognizing peptide-MHC complexes on target cells, or indirectly, by secret- ing cytokines capable of signaling through death recaptors expressed on the target cell surface. Autoreactive CD8+T cells can also contribute to autoimmunity by releasing cytokines capable of increasing the susceptibility of target cells to cytotoxicity, or by secreting chemokines that attract other immune cells to the site of autoimmu- nity. Autoreactive CD8+ T cells can also downregulate autoimmune responses. Recent important advances in- clude a mechanistic understanding of events leading to the activation and recruitment of autoreactive CD8+T cells in certain autoimmune responses and a greater appreciation of the diverse roles that these T cells play in autoimmunity. ( J Intern Med Taiwan 2006; 17: 212-220 )