Co-receptor Choice by V Alpha14i NKT Cells is Driven by Th-POK Expression Rather Than Avoidance of CD8-mediated Negative Selection

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2010 Apr 21

PMID 20404101

Citations 37

Authors

Isaac Engel

Kirsten Hammond

Barbara A Sullivan

Xi He

Ichiro Taniuchi

Dietmar Kappes

Mitchell Kronenberg

Affiliations

Soon will be listed here.

Abstract

Mouse natural killer T (NKT) cells with an invariant V alpha14-J alpha18 rearrangement (V alpha14 invariant [V alpha14i] NKT cells) are either CD4(+)CD8(-) or CD4(-)CD8(-). Because transgenic mice with forced CD8 expression in all T cells exhibited a profound NKT cell deficit, the absence of CD8 has been attributed to negative selection. We now present evidence that CD8 does not serve as a coreceptor for CD1d recognition and that the defect in development in CD8 transgene homozygous mice is the result of a reduction in secondary T cell receptor alpha rearrangements. Thymocytes from mice hemizygous for the CD8 transgene have a less severe rearrangement defect and have functional CD8(+) V alpha14i NKT cells. Furthermore, we demonstrate that the transcription factor Th, Poxviruses and Zinc finger, and Krüppel family (Th-POK) is expressed by V alpha14i NKT cells throughout their differentiation and is necessary both to silence CD8 expression and for the functional maturity of V alpha14i NKT cells. We therefore suggest that Th-POK expression is required for the normal development of V alpha14i NKT cells and that the absence of CD8 expression by these cells is a by-product of such expression, as opposed to the result of negative selection of CD8-expressing V alpha14i NKT cells.

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References

Leishman A, Naidenko O, Attinger A, Koning F, Lena C, Xiong Y . T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule, TL. Science. 2001; 294(5548):1936-9. DOI: 10.1126/science.1063564. View

Pear W, Miller J, Xu L, Pui J, Soffer B, Quackenbush R . Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood. 1998; 92(10):3780-92. View

Vugmeyster Y, Glas R, Perarnau B, Lemonnier F, Eisen H, Ploegh H . Major histocompatibility complex (MHC) class I KbDb -/- deficient mice possess functional CD8+ T cells and natural killer cells. Proc Natl Acad Sci U S A. 1998; 95(21):12492-7. PMC: 22858. DOI: 10.1073/pnas.95.21.12492. View

Dave V, Allman D, Keefe R, Hardy R, Kappes D . HD mice: a novel mouse mutant with a specific defect in the generation of CD4(+) T cells. Proc Natl Acad Sci U S A. 1998; 95(14):8187-92. PMC: 20951. DOI: 10.1073/pnas.95.14.8187. View

Matsuda J, Gapin L . Developmental program of mouse Valpha14i NKT cells. Curr Opin Immunol. 2005; 17(2):122-30. DOI: 10.1016/j.coi.2005.01.002. View

Kinsella T, Nolan G . Episomal vectors rapidly and stably produce high-titer recombinant retrovirus. Hum Gene Ther. 1996; 7(12):1405-13. DOI: 10.1089/hum.1996.7.12-1405. View

Loza M, Metelitsa L, Perussia B . NKT and T cells: coordinate regulation of NK-like phenotype and cytokine production. Eur J Immunol. 2002; 32(12):3453-62. DOI: 10.1002/1521-4141(200212)32:12<3453::AID-IMMU3453>3.0.CO;2-D. View

Wack A, Coles M, Norton T, HOSTERT A, Kioussis D . Early onset of CD8 transgene expression inhibits the transition from DN3 to DP thymocytes. J Immunol. 2000; 165(3):1236-42. DOI: 10.4049/jimmunol.165.3.1236. View

Brossay L, Tangri S, Bix M, Cardell S, Locksley R, Kronenberg M . Mouse CD1-autoreactive T cells have diverse patterns of reactivity to CD1+ targets. J Immunol. 1998; 160(8):3681-8. View

10.

Setoguchi R, Tachibana M, Naoe Y, Muroi S, Akiyama K, Tezuka C . Repression of the transcription factor Th-POK by Runx complexes in cytotoxic T cell development. Science. 2008; 319(5864):822-5. DOI: 10.1126/science.1151844. View

11.

Lantz O, Bendelac A . An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans. J Exp Med. 1994; 180(3):1097-106. PMC: 2191643. DOI: 10.1084/jem.180.3.1097. View

12.

Schumann J, Mycko M, Dellabona P, Casorati G, MacDonald H . Cutting edge: influence of the TCR Vbeta domain on the selection of semi-invariant NKT cells by endogenous ligands. J Immunol. 2006; 176(4):2064-8. DOI: 10.4049/jimmunol.176.4.2064. View

13.

Fisher D, Hunt 3rd S, Hood L . Structure of a gene encoding a murine thymus leukemia antigen, and organization of Tla genes in the BALB/c mouse. J Exp Med. 1985; 162(2):528-45. PMC: 2187753. DOI: 10.1084/jem.162.2.528. View

14.

Wang L, Wildt K, Castro E, Xiong Y, Feigenbaum L, Tessarollo L . The zinc finger transcription factor Zbtb7b represses CD8-lineage gene expression in peripheral CD4+ T cells. Immunity. 2008; 29(6):876-87. PMC: 3392968. DOI: 10.1016/j.immuni.2008.09.019. View

15.

Garcia K, Scott C, Brunmark A, Carbone F, Peterson P, Wilson I . CD8 enhances formation of stable T-cell receptor/MHC class I molecule complexes. Nature. 1996; 384(6609):577-81. DOI: 10.1038/384577a0. View

16.

Egawa T, Eberl G, Taniuchi I, Benlagha K, Geissmann F, Hennighausen L . Genetic evidence supporting selection of the Valpha14i NKT cell lineage from double-positive thymocyte precursors. Immunity. 2005; 22(6):705-16. DOI: 10.1016/j.immuni.2005.03.011. View

17.

Teitell M, Holcombe H, Brossay L, Hagenbaugh A, Jackson M, Pond L . Nonclassical behavior of the mouse CD1 class I-like molecule. J Immunol. 1997; 158(5):2143-9. View

18.

Berzins S, Cochrane A, Pellicci D, Smyth M, Godfrey D . Limited correlation between human thymus and blood NKT cell content revealed by an ontogeny study of paired tissue samples. Eur J Immunol. 2005; 35(5):1399-407. DOI: 10.1002/eji.200425958. View

19.

He X, Park K, Wang H, He X, Zhang Y, Hua X . CD4-CD8 lineage commitment is regulated by a silencer element at the ThPOK transcription-factor locus. Immunity. 2008; 28(3):346-58. DOI: 10.1016/j.immuni.2008.02.006. View

20.

He X, He X, Dave V, Zhang Y, Hua X, Nicolas E . The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature. 2005; 433(7028):826-33. DOI: 10.1038/nature03338. View