The peripheral differentiation of human natural killer T cells

The peripheral maturation of human CD1d‐restricted natural killer T (NKT) cells has not been well described. In this study, we identified four major subsets of NKT cells in adults, distinguished by the expression of CD4, CD8 and CCR5. Phenotypic analysis suggested a hierarchical pattern of differentiation, whereby immature CD4+CD8−CCR5− cells progressed to an intermediate CD4+CD8−CCR5+ stage, which remained less differentiated than the CD4−CD8− and CD4−CD8+ subsets, both of which expressed CCR5. This interpretation was supported by functional data, including clonogenic potential and cytokine secretion profiles, as well as T‐cell receptor (TCR) excision circle analysis. Moreover, conventional and high‐throughput sequencing of the corresponding TCR repertoires demonstrated significant clonotypic overlap within individuals, especially between the more differentiated CD4−CD8− and CD4−CD8+ subsets. Collectively, these results mapped a linear differentiation pathway across the post‐thymic landscape of human CD1d‐restricted NKT cells.

[1]  A. Shalek,et al.  Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells , 2017, Cell.

[2]  H. Ploegh,et al.  Monoclonal Invariant NKT (iNKT) Cell Mice Reveal a Role for Both Tissue of Origin and the TCR in Development of iNKT Functional Subsets , 2017, The Journal of Immunology.

[3]  M. Weirauch,et al.  Multiple layers of transcriptional regulation by PLZF in NKT-cell development , 2016, Proceedings of the National Academy of Sciences.

[4]  S. Jameson,et al.  Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response. , 2015, Immunity.

[5]  A. Singer,et al.  Let-7 miRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function , 2015, Nature Immunology.

[6]  S. Berzins,et al.  Natural killer T cells: drivers or passengers in preventing human disease? , 2014, Nature Reviews Immunology.

[7]  Sam Darko,et al.  Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development. , 2014, The Journal of allergy and clinical immunology.

[8]  D. Doherty,et al.  Human Invariant NKT Cell Subsets Differentially Promote Differentiation, Antibody Production, and T Cell Stimulation by B Cells In Vitro , 2013, The Journal of Immunology.

[9]  L. Harrison,et al.  Ex‐vivo analysis of human Natural Killer T cells demonstrates heterogeneity between tissues and within established CD4+ and CD4− subsets , 2013, Clinical and experimental immunology.

[10]  Benedict Ng,et al.  NKT and MAIT invariant TCRα sequences can be produced efficiently by VJ gene recombination. , 2013, Immunobiology.

[11]  P. Brennan,et al.  Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions , 2013, Nature Reviews Immunology.

[12]  J. Rossjohn,et al.  Recognition of CD1d-restricted antigens by natural killer T cells , 2012, Nature Reviews Immunology.

[13]  Ann Atzberger,et al.  Distinct and Overlapping Effector Functions of Expanded Human CD4+, CD8α+ and CD4-CD8α- Invariant Natural Killer T Cells , 2011, PloS one.

[14]  D. Douek,et al.  Unbiased Molecular Analysis of T Cell Receptor Expression Using Template‐Switch Anchored RT‐PCR , 2011, Current protocols in immunology.

[15]  F. Marincola,et al.  A human memory T-cell subset with stem cell-like properties , 2011, Nature Medicine.

[16]  J. Heinrich,et al.  Cord Blood Vα24-Vβ11+ Natural Killer T Cells Display a Th2-Chemokine Receptor Profile and Cytokine Responses , 2011, PloS one.

[17]  D. Godfrey,et al.  Raising the NKT cell family , 2010, Nature Immunology.

[18]  Kumud Kumari,et al.  Characterization of human invariant natural killer T subsets in health and disease using a novel invariant natural killer T cell‐clonotypic monoclonal antibody, 6B11 , 2007, Immunology.

[19]  M. Taniguchi,et al.  Functionally distinct NKT cell subsets and subtypes , 2005, The Journal of experimental medicine.

[20]  S. Migueles,et al.  Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses , 2005, The Journal of experimental medicine.

[21]  D. Wei,et al.  Characterization of the early stages of thymic NKT cell development , 2005, The Journal of experimental medicine.

[22]  D. Pellicci,et al.  Limited correlation between human thymus and blood NKT cell content revealed by an ontogeny study of paired tissue samples , 2005, European journal of immunology.

[23]  K. Weinberg,et al.  Distinct homeostatic requirements of CD4+ and CD4- subsets of Valpha24-invariant natural killer T cells in humans. , 2004, Blood.

[24]  P. Chattopadhyay,et al.  Seventeen-colour flow cytometry: unravelling the immune system , 2004, Nature Reviews Immunology.

[25]  D. Nixon,et al.  Development of innate CD4+ α-chain variable gene segment 24 (Vα24) natural killer T cells in the early human fetal thymus is regulated by IL-7 , 2004 .

[26]  L. Kaer,et al.  NKT cells: what's in a name? , 2004, Nature Reviews Immunology.

[27]  P. Rogers,et al.  Expansion of human Vα24+ NKT cells by repeated stimulation with KRN7000 , 2004 .

[28]  S. Porcelli,et al.  Control of NKT Cell Differentiation by Tissue-Specific Microenvironments 1 , 2003, The Journal of Immunology.

[29]  J. Strominger,et al.  CD1d-Restricted NKT Cells Express a Chemokine Receptor Profile Indicative of Th1-Type Inflammatory Homing Cells 1 , 2003, The Journal of Immunology.

[30]  E. Butcher,et al.  Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among Vα24+Vβ11+ NKT cell subsets with distinct cytokine-producing capacity , 2002 .

[31]  D. Pellicci,et al.  A Natural Killer T (NKT) Cell Developmental Pathway Involving a Thymus-dependent NK1.1−CD4+ CD1d-dependent Precursor Stage , 2002, The Journal of experimental medicine.

[32]  Daniel C. Douek,et al.  A Novel Approach to the Analysis of Specificity, Clonality, and Frequency of HIV-Specific T Cell Responses Reveals a Potential Mechanism for Control of Viral Escape1 , 2002, The Journal of Immunology.

[33]  L. Teyton,et al.  A Thymic Precursor to the NK T Cell Lineage , 2002, Science.

[34]  L. Teyton,et al.  Distinct Functional Lineages of Human Vα24 Natural Killer T Cells , 2002, The Journal of experimental medicine.

[35]  Takashi Yamamura,et al.  Functionally Distinct Subsets of CD1d-restricted Natural Killer T Cells Revealed by CD1d Tetramer Staining , 2002, The Journal of experimental medicine.

[36]  N. Fazilleau,et al.  Natural killer T cells reactive to a single glycolipid exhibit a highly diverse T cell receptor β repertoire and small clone size , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[37]  A. Fersht,et al.  Human CD1d–glycolipid tetramers generated by in vitro oxidative refolding chromatography , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Kronenberg,et al.  Tracking the Response of Natural Killer T Cells to a Glycolipid Antigen Using Cd1d Tetramers , 2000, The Journal of experimental medicine.

[39]  P. Klenerman,et al.  Cytotoxic T lymphocytes, chemokines and antiviral immunity. , 1999, Immunology today.

[40]  Louis J. Picker,et al.  Changes in thymic function with age and during the treatment of HIV infection , 1998, Nature.

[41]  O. Lantz,et al.  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 , 1994, The Journal of experimental medicine.

[42]  A. Lanzavecchia,et al.  An invariant V alpha 24-J alpha Q/V beta 11 T cell receptor is expressed in all individuals by clonally expanded CD4-8- T cells , 1994, The Journal of experimental medicine.

[43]  S. Balk,et al.  Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T cells demonstrates preferential use of several V beta genes and an invariant TCR alpha chain , 1993, The Journal of experimental medicine.

[44]  Marie-Paule Lefranc,et al.  IMGT, the international ImMunoGeneTics database , 1999, Nucleic Acids Res..