IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection

被引：49

作者：

Beltra, Jean-Christophe ^{[1
,2
]}

Bourbonnais, Sara ^{[1
]}

Bedard, Nathalie ^{[3
]}

Charpentier, Tania ^{[4
]}

Boulange, Moana ^{[1
,2
]}

Michaud, Eva ^{[1
,2
]}

Boufaied, Ines ^{[5
]}

Bruneau, Julie ^{[3
,6
]}

Shoukry, Naglaa H. ^{[3
,7
]}

Lamarre, Alain ^{[4
]}

Decaluwe, Helene ^{[1
,2
,8
]}

机构：

[1] St Justine Univ Hosp, Res Ctr, Cytokines & Adapt Immun Lab, Montreal, PQ H3T 1C5, Canada

[2] Univ Montreal, Fac Med, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada

[3] Univ Montreal Hosp, Res Ctr, Montreal, PQ H2X 0A9, Canada

[4] Inst Armand Frappier, Inst Natl Rech Sci, Immunovirol Lab, Laval, PQ H7V 1B7, Canada

[5] St Justine Univ Hosp, Res Ctr, Flow Cytometry Platform, Montreal, PQ H3T 1C5, Canada

[6] Univ Montreal, Fac Med, Dept Family Med & Emergency Med, Montreal, PQ H2X 0A9, Canada

[7] Univ Montreal, Fac Med, Dept Med, Montreal, PQ H3T 1J4, Canada

[8] Univ Montreal, Fac Med, Dept Pediat, Immunol & Rheumatol Div, Montreal, PQ H3T 1C5, Canada

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2016年 / 113卷 / 37期

基金：

加拿大健康研究院;

关键词：

CD8 T cell; IL-2; IL-15; exhaustion; memory T cell; CD8(+) T-CELLS; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; INHIBITORY RECEPTOR PD-1; EFFECTOR; IL-2; DIFFERENTIATION; EXPRESSION; GENERATION; RESPONSES; CYTOKINES;

D O I：

10.1073/pnas.1604256113

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Exhaustion of CD8(+) T cells severely impedes the adaptive immune response to chronic viral infections. Despite major advances in our understanding of the molecular regulation of exhaustion, the cytokines that directly control this process during chronicity remain unknown. We demonstrate a direct impact of IL-2 and IL-15, two common gamma-chain-dependent cytokines, on CD8(+) T-cell exhaustion. Common to both cytokine receptors, the IL-2 receptor beta (IL2R beta) chain is selectively maintained on CD8(+) T cells during chronic lymphocytic choriomeningitis virus and hepatitis C virus infections. Its expression correlates with exhaustion severity and identifies terminally exhausted CD8(+) T cells both in mice and humans. Genetic ablation of the IL2R beta chain on CD8(+) T cells restrains inhibitory receptor induction, in particular 2B4 and Tim-3; precludes terminal differentiation of highly defective PD-1(hi) effectors; and rescues memory T-cell development and responsiveness to IL-7-dependent signals. Together, we ascribe a previously unexpected role to IL-2 and IL-15 as instigators of CD8(+) T-cell exhaustion during chronic viral infection.

引用

页码：E5444 / E5453

页数：10

共 45 条

[1] Progressive Loss of Memory T Cell Potential and Commitment to Exhaustion during Chronic Viral Infection [J].

Angelosanto, Jill M. ;

Blackburn, Shawn D. ;

Crawford, Alison ;

Wherry, E. John .

JOURNAL OF VIROLOGY, 2012, 86 (15) :8161-8170

[2] Cutting Edge: The Transcription Factor Eomesodermin Enables CD8+ T Cells To Compete for the Memory Cell Niche [J].

Banerjee, Arnob ;

Gordon, Scott M. ;

Intlekofer, Andrew M. ;

Paley, Michael A. ;

Mooney, Erin C. ;

Lindsten, Tulia ;

Wherry, E. John ;

Reiner, Steven L. .

JOURNAL OF IMMUNOLOGY, 2010, 185 (09) :4988-4992

[3] Restoring function in exhausted CD8 T cells during chronic viral infection [J].

Barber, DL ;

Wherry, EJ ;

Masopust, D ;

Zhu, BG ;

Allison, JP ;

Sharpe, AH ;

Freeman, GJ ;

Ahmed, R .

NATURE, 2006, 439 (7077) :682-687

[4] QUANTIFICATION OF LYMPHOCYTIC CHORIOMENINGITIS VIRUS WITH AN IMMUNOLOGICAL FOCUS ASSAY IN 24-WELL OR 96-WELL PLATES [J].

BATTEGAY, M ;

COOPER, S ;

ALTHAGE, A ;

BANZIGER, J ;

HENGARTNER, H ;

ZINKERNAGEL, RM .

JOURNAL OF VIROLOGICAL METHODS, 1991, 33 (1-2) :191-198

[5] Cytokines and persistent viral infections [J].

Beltra, Jean-Christophe ;

Decaluwe, Helene .

CYTOKINE, 2016, 82 :4-15

[6] Interleukin-2 Tickles T Cell Memory [J].

Belz, Gabrielle T. ;

Masson, Frederick .

IMMUNITY, 2010, 32 (01) :7-9

[7] Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection [J].

Blackburn, Shawn D. ;

Shin, Haina ;

Haining, W. Nicholas ;

Zou, Tao ;

Workman, Creg J. ;

Polley, Antonio ;

Betts, Michael R. ;

Freeman, Gordon J. ;

Vignali, Dario A. A. ;

Wherry, E. John .

NATURE IMMUNOLOGY, 2009, 10 (01) :29-37

[8] Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade [J].

Blackburn, Shawn D. ;

Shin, Haina ;

Freeman, Gordon J. ;

Wherry, E. John .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (39) :15016-15021

[9] Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection [J].

Brooks, DG ;

Teyton, L ;

Oldstone, MBA ;

McGavern, DB .

JOURNAL OF VIROLOGY, 2005, 79 (16) :10514-10527

[10] Generation of effector CD8+T cells and their conversion to memory T cells [J].

Cui, Weiguo ;

Kaech, Susan M. .

IMMUNOLOGICAL REVIEWS, 2010, 236 :151-166

← 1 2 3 4 5 →