The CD4- CD8- MAIT cell subpopulation is a functionally distinct subset developmentally related to the main CD8+ MAIT cell pool

被引：129

作者：

Dias, Joana ^{[1
]}

Boulouis, Caroline ^{[1
]}

Gorin, Jean-Baptiste ^{[1
]}

van den Biggelaar, Robin H. G. A. ^{[1
,2
]}

Lal, Kerri G. ^{[1
,3
,4
]}

Gibbs, Anna ^{[5
]}

Loh, Liyen ^{[6
,7
]}

Gulam, Muhammad Yaaseen ^{[8
]}

Sia, Wan Rong ^{[8
]}

Bari, Sudipto ^{[9
]}

Hwang, William Y. K. ^{[9
,10
,11
]}

Nixon, Douglas F. ^{[6
,12
]}

Nguyen, Son ^{[13
]}

Betts, Michael R. ^{[13
]}

Buggert, Marcus ^{[1
,13
]}

Eller, Michael A. ^{[3
,4
]}

Broliden, Kristina ^{[5
]}

Tjernlund, Annelie ^{[5
]}

Sandberg, Johan K. ^{[1
]}

Leeansyah, Edwin ^{[1
,8
]}

机构：

[1] Karolinska Inst, Karolinska Univ Hosp Huddinge, Ctr Infect Med, Dept Med, S-14186 Stockholm, Sweden

[2] Univ Utrecht, Dept Infect Dis & Immunol, NL-3584CL Utrecht, Netherlands

[3] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA

[4] Henry M Jackson Fdn Adv Mil Med, Dept Retrovirol, Bethesda, MD 20817 USA

[5] Karolinska Univ Hosp Solna, Karolinska Inst, Ctr Mol Med, Unit Infect Dis,Dept Med Solna, S-17176 Stockholm, Sweden

[6] Univ Calif San Francisco, Dept Med, Div Expt Med, San Francisco, CA 94110 USA

[7] Univ Melbourne, Dept Microbiol & Immunol, Melbourne, Vic 3010, Australia

[8] Duke Natl Univ Singapore, Med Sch, Program Emerging Infect Dis, Singapore 169587, Singapore

[9] Singapore Gen Hosp, Dept Hematol, Singapore 169608, Singapore

[10] Natl Canc Ctr Singapore, Div Med Sci, Singapore 16910, Singapore

[11] Duke Natl Univ Singapore, Med Sch, Program Canc & Stem Cell Biol, Singapore 16958, Singapore

[12] George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC 20052 USA

[13] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2018年 / 115卷 / 49期

基金：

美国国家卫生研究院; 瑞典研究理事会;

关键词：

MAIT cells; MR1; CD8; apoptosis; functional heterogeneity; INVARIANT T-CELLS; CYTOKINE PRODUCTION; ACTIVATION; HETEROGENEITY; BLOOD; VIVO; RESPONSES; SELECTION; LIVER; IL-17;

D O I：

10.1073/pnas.1812273115

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：

Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin metabolites presented by the MHC class I-like protein MR1. Human MAIT cells predominantly express the CD8 alpha coreceptor (CD8(+)), with a smaller subset lacking both CD4 and CD8 (double-negative, DN). However, it is unclear if these two MAIT cell subpopulations distinguished by CD8a represent functionally distinct subsets. Here, we show that the two MAIT cell subsets express divergent transcriptional programs and distinct patterns of classic T cell transcription factors. Furthermore, CD8(+) MAIT cells have higher levels of receptors for IL-12 and IL-18, as well as of the activating receptors CD2, CD9, and NKG2D, and display superior functionality following stimulation with riboflavin-autotrophic as well as riboflavin-auxotrophic bacterial strains. DN MAIT cells display higher ROR gamma t/T-bet ratio, and express less IFN-gamma and more IL-17. Furthermore, the DN subset displays enrichment of an apoptosis gene signature and higher propensity for activation-induced apoptosis. During development in human fetal tissues, DN MAIT cells are more mature and accumulate over gestational time with reciprocal contraction of the CD8(+) subset. Analysis of the T cell receptor repertoire reveals higher diversity in CD8(+) MAIT cells than in DN MAIT cells. Finally, chronic T cell receptor stimulation of CD8(+) MAIT cells in an in vitro culture system supports the accumulation and maintenance of the DN subpopulation. These findings define human CD8(+) and DN MAIT cells as functionally distinct subsets and indicate a derivative developmental relationship.

引用

页码：E11513 / E11522

页数：10

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