Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

被引：69

作者：

Tonnerre, Pierre ^{[1
,2
,3
]}

Wolski, David ^{[1
,2
]}

Subudhi, Sonu ^{[1
,2
]}

Al-Jabban, Jihad ^{[1
,2
]}

Hoogeveen, Ruben C. ^{[1
,2
]}

Damasio, Marcos ^{[1
,2
]}

Drescher, Hannah K. ^{[1
,2
]}

Bartsch, Lea M. ^{[1
,2
]}

Tully, Damien C. ^{[4
]}

Sen, Debattama R. ^{[5
,6
]}

Bean, David J. ^{[4
]}

Brown, Joelle ^{[1
,2
]}

Torres-Cornejo, Almudena ^{[1
,2
]}

Robidoux, Maxwell ^{[1
,2
]}

Kvistad, Daniel ^{[1
,2
]}

Alatrakchi, Nadia ^{[1
,2
]}

Cui, Ang ^{[7
,8
]}

Lieb, David ^{[7
]}

Cheney, James A. ^{[1
,2
]}

Gustafson, Jenna ^{[1
,2
]}

Lewis-Ximenez, Lia L. ^{[9
]}

Massenet-Regad, Lucile ^{[3
]}

Eisenhaure, Thomas ^{[7
]}

Aneja, Jasneet ^{[1
,2
,10
]}

Haining, W. Nicholas ^{[5
,6
]}

Chung, Raymond T. ^{[1
,2
]}

Hacohen, Nir ^{[7
,11
]}

Allen, Todd M. ^{[4
]}

Kim, Arthur Y. ^{[2
,10
]}

Lauer, Georg M. ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA

[2] Harvard Med Sch, Boston, MA 02115 USA

[3] Univ Paris, Inserm U976, Inst Rech St Louis, Paris, France

[4] MIT & Harvard, Ragon Inst MGH, Cambridge, MA USA

[5] Harvard Med Sch, Div Med Sci, Boston, MA 02115 USA

[6] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[7] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[8] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA

[9] Fundacao Oswaldo Cruz, Inst Oswaldo Cruz, Rio De Janeiro, Brazil

[10] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA

[11] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

来源：

NATURE IMMUNOLOGY | 2021年 / 22卷 / 08期

关键词：

PD-1; EXPRESSION; RNA-SEQ; PERSISTENCE; LYMPHOCYTES; INFECTION;

D O I：

10.1038/s41590-021-00982-6

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8(+) T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory. Lauer and colleagues examine CD8(+) T cells following cure of human hepatitis C virus (HCV) infection. CD8(+) T cells exposed to chronic HCV-specific activation show durable functional, phenotypic and transcriptional exhaustion that is maintained even after antigen stimulus is removed.

引用

页码：1030 / +

页数：30

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