Skip to main content

Main menu

  • Home
  • Articles
    • Current Issue
    • Next in The JI
    • Archive
    • Brief Reviews
    • Pillars of Immunology
    • Translating Immunology
    • Most Read
    • Top Downloads
    • Annual Meeting Abstracts
  • COVID-19/SARS/MERS Articles
  • Info
    • About the Journal
    • For Authors
    • Journal Policies
    • Influence Statement
    • For Advertisers
  • Editors
  • Submit
    • Submit a Manuscript
    • Instructions for Authors
    • Journal Policies
  • Subscribe
    • Journal Subscriptions
    • Email Alerts
    • RSS Feeds
    • ImmunoCasts
  • More
    • Most Read
    • Most Cited
    • ImmunoCasts
    • AAI Disclaimer
    • Feedback
    • Help
    • Accessibility Statement
  • Other Publications
    • American Association of Immunologists
    • ImmunoHorizons

User menu

  • Subscribe
  • Log in

Search

  • Advanced search
The Journal of Immunology
  • Other Publications
    • American Association of Immunologists
    • ImmunoHorizons
  • Subscribe
  • Log in
The Journal of Immunology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Next in The JI
    • Archive
    • Brief Reviews
    • Pillars of Immunology
    • Translating Immunology
    • Most Read
    • Top Downloads
    • Annual Meeting Abstracts
  • COVID-19/SARS/MERS Articles
  • Info
    • About the Journal
    • For Authors
    • Journal Policies
    • Influence Statement
    • For Advertisers
  • Editors
  • Submit
    • Submit a Manuscript
    • Instructions for Authors
    • Journal Policies
  • Subscribe
    • Journal Subscriptions
    • Email Alerts
    • RSS Feeds
    • ImmunoCasts
  • More
    • Most Read
    • Most Cited
    • ImmunoCasts
    • AAI Disclaimer
    • Feedback
    • Help
    • Accessibility Statement
  • Follow The Journal of Immunology on Twitter
  • Follow The Journal of Immunology on RSS

When Less Is More: T Lymphocyte Populations with Restricted Antigen Receptor Diversity

Mitchell Kronenberg
J Immunol August 1, 2014, 193 (3) 975-976; DOI: https://doi.org/10.4049/jimmunol.1401491
Mitchell Kronenberg
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Two papers highlighted here as Pillars of Immunology led to the discovery, more than two decades ago, of expanded T lymphocyte populations with a limited TCR α-chain diversity (1, 2). This would be a mere factoid if these specialized cell populations were not highly conserved, suggestive of their important function, if they did not behave differently from mainstream T lymphocytes, and, also, if they did not influence many immune responses. One of these populations is known as type I or invariant NKT (iNKT) cells, and the other is known as mucosal-associated invariant T (MAIT) cells.

The first characterized population of T lymphocytes with an invariant Ag receptor was mouse γδ T cells that are found in several epithelial tissues, particularly the skin (3). This population is not found in humans, and its lack of conservation stands in contrast to iNKT and MAIT cells, which are found in most mammals (4). iNKT cells and MAIT cells are expanded T lymphocyte populations, with members of each population having identical or similar Ag specificities. Many of these cells are found in tissues such as liver, lung, and intestine, and, importantly, these lymphocytes respond rapidly to Ag stimulation, similar to innate immune cells (4). Key findings in understanding their specificity that came later include the discovery of their selecting class I–like Ag-presenting molecules, CD1d for iNKT cells (5) and MR1 for MAIT cells (6). Another key finding was the identification of the nonpeptidic molecules these class I–like molecules present: glycolipids and phospholipids for iNKT cells (7) and microbial riboflavin metabolites for MAIT cells (8). Although it is difficult to identify a singular finding regarding these two interesting T cell populations, it is important to highlight the early discovery of lymphocytes with restricted TCR α diversity, which helped to catalyze the broad interest in these cells.

Masaru Taniguchi and colleagues (9) had characterized a mouse TCR α-chain joining Vα14–Jα281, later Vα14–Jα18, which was used by a number of T cell hybridomas reported to be specific for keyhole limpet hemocyanin and alleged to have suppressor activity. This is the well-known TCR α-chain that characterizes iNKT cells. In the study highlighted from 1990 (1), they used PCR with Vα14 and Cα primers, followed by DNA sequencing, to show that the rearrangement found in the hybridomas was prevalent in the spleen and thymus. They corroborated this with RNase protection assays using probes that spanned the Vα–Jα junction, and they estimated that cells expressing this α gene rearrangement were surprisingly prevalent, that is, 0.7% of mouse thymocytes and 1.5% of splenic T cells. The transcript appeared in cells from mice at 2 wk of age and reached a plateau at 5 wk. These findings match reasonably well with later measurements of iNKT cells done with CD1d tetramers (10, 11). Haruhiko Koseki et al. (1) also observed that the abundance of mRNA from this rearrangement did not vary when congenic mouse strains with different MHC haplotypes were analyzed. They therefore suggested that cells with this TCR recognize a nonpolymorphic class I molecule, and they offered the prescient speculation that these cells might be autoreactive. T cell suppression, as described in the 1980s and earlier, has for good reasons not survived as part of the canon of contemporary immunology, and based on their TCR, the suggested keyhole limpet hemocyanin specificity of the hybridomas in the paper by Koseki et al. is not likely. Regardless, most of the findings described by Koseki et al. are on the mark in establishing the unexpected prevalence of the Vα14–Jα14 TCR rearrangement.

Missing from this study, however, was insight into the type of T cells expressing this invariant α-chain. Olivier Lantz and Albert Bendelac (12) later made the first characterization of the thymocytes expressing a Vα14–Jα18 TCR. They showed that these cells are a subset that requires β2-microglobulin and therefore is dependent on class I Ag-presenting molecules. They also demonstrated that these cells express the NK receptor NK1.1 along with a high level of CD44, a marker for activated or memory cells. Furthermore, they are either CD4+ or CD4−CD8− double negative (DN) (12). By analyzing hybridomas made from CD44highCD4+ or DN thymocytes, they found that the TCR β-chain genes they expressed rearranged Vβ8.2, Vβ7, or Vβ2, but with diverse Vβ–Jβ sequences.

The second Pillars of Immunology paper reports research on human cells from 1993 by Steven Balk and colleagues (2). In this report, Steven Porcelli et al. focused on DN αβ TCR lymphocytes because of a possible connection of these cells to autoimmune disease pathogenesis, as well as the finding that some DN T lymphocytes were reactive to mycobacterial Ags presented by the nonclassical class I molecule CD1b (13). They used denaturing gel electrophoresis, quantitative PCR, and cloning and sequencing to show that two invariant TCR rearrangements were prevalent in DN T cells from multiple donors. One of these joined Vα24 to JαQ (Vα24–Jα18 or TRAV10–TRAJ18), subsequently identified as the rearrangement in human iNKT cells (14). Antonio Lanzavecchia and colleagues (15) reported a similar finding based on the analysis of DN αβ TCR lymphocytes essentially at the same time. All of the laboratories involved noted the sequence similarity of this human TCR α rearrangement to the one reported earlier in mice (2, 12, 15). Interestingly, Porcelli et al. found a second prevalent rearrangement in the DN T cells, joining Vα7.2 to IGRJa14, later called Jα33 (TRAV1-2–TRAJ33). This rearrangement had a greater degree of diversity in the Vα–Jα junction encoding the CDR3 region than did the iNKT cell α-chain, and it is the one that Lantz and colleagues (16) later showed is characteristic of MAIT cells. Porcelli et al. demonstrated that the DN αβ TCR population has preferential transcription of a rearranged Vβ11 segment, which is similar to mouse Vβ8.2, the most prevalent Vβ gene expressed by mouse iNKT cells. Vβ2 and Vβ13 also were enriched in DN αβ T cells, and these later were shown to be prevalent in MAIT cells (16). Analysis on polyacrylamide gels indicated that, as in the mouse, the β-chain rearrangements were more diverse than those of the α-chains. This study only analyzed polyclonal DN αβ T cells, however, and therefore it could not determine which TCR β-chains were paired with the α-chains with limited diversity. In a second study from the Lanzavecchia group, Paolo Dellabona et al. (17) produced Abs to Vβ11 and Vα24 and showed that these are coexpressed in human DN T cells.

Although innate immune cells respond very rapidly, evolution does not shy away from redundancy in the immune system, and it has generated prevalent populations of T lymphocytes with a highly restricted Ag receptor diversity, tissue residence, and rapid response kinetics, similar to innate immune cells. Although there are some striking similarities between the two populations, iNKT cells are prevalent in mice and MAIT cells are relatively infrequent, whereas the opposite pattern holds true in humans, with MAIT cells being much more prevalent (4). Another distinction is that iNKT cells can respond to microbial and self-antigens but do not completely depend on microbes for their homeostasis (18), whereas MAIT cells are known to respond only to microbial metabolites of riboflavin (8), and unlike iNKT cells, they are absent in germ-free mice (6). Furthermore, recent evidence has suggested that there are functional subsets of iNKT cells analogous to Th1, Th2, and Th17 CD4+ helper T cells (19, 20), whereas MAIT cells do not produce Th2 cytokines (21). Understanding the myriad effects of iNKT cells on the immune system remains an area of very active investigation, and although there are many fewer studies of MAIT cell function, this area is emerging, aided by the development of defined Ags and MR1 tetramers (22). The findings in these seminal papers from two decades ago helped to open up the vigorous fields of research on these two specialized lymphocyte populations by making the unexpected observation that some αβ TCRs are surprisingly prevalent in all individuals.

Disclosures

The author has no financial conflicts of interest.

Footnotes

  • Abbreviations used in this article:

    DN
    double negative
    iNKT
    invariant NKT
    MAIT
    mucosal-associated invariant T.

  • Copyright © 2014 by The American Association of Immunologists, Inc.

References

  1. ↵
    1. Koseki H.,
    2. K. Imai,
    3. F. Nakayama,
    4. T. Sado,
    5. K. Moriwaki,
    6. M. Taniguchi
    . 1990. Homogenous junctional sequence of the V14+ T-cell antigen receptor alpha chain expanded in unprimed mice. Proc. Natl. Acad. Sci. USA 87: 5248–5252.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Porcelli S.,
    2. C. E. Yockey,
    3. M. B. Brenner,
    4. S. P. Balk
    . 1993. 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. J. Exp. Med. 178: 1–16.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Asarnow D. M.,
    2. W. A. Kuziel,
    3. M. Bonyhadi,
    4. R. E. Tigelaar,
    5. P. W. Tucker,
    6. J. P. Allison
    . 1988. Limited diversity of γδ antigen receptor genes of Thy-1+ dendritic epidermal cells. Cell 55: 837–847.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Salio M.,
    2. J. D. Silk,
    3. E. Y. Jones,
    4. V. Cerundolo
    . 2014. Biology of CD1- and MR1-restricted T cells. Annu. Rev. Immunol. 32: 323–366.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Bendelac A.,
    2. O. Lantz,
    3. M. E. Quimby,
    4. J. W. Yewdell,
    5. J. R. Bennink,
    6. R. R. Brutkiewicz
    . 1995. CD1 recognition by mouse NK1+ T lymphocytes. Science 268: 863–865.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Treiner E.,
    2. L. Duban,
    3. S. Bahram,
    4. M. Radosavljevic,
    5. V. Wanner,
    6. F. Tilloy,
    7. P. Affaticati,
    8. S. Gilfillan,
    9. O. Lantz
    . 2003. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422: 164–169.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Kawano T.,
    2. J. Cui,
    3. Y. Koezuka,
    4. I. Toura,
    5. Y. Kaneko,
    6. K. Motoki,
    7. H. Ueno,
    8. R. Nakagawa,
    9. H. Sato,
    10. E. Kondo,
    11. et al
    . 1997. CD1d-restricted and TCR-mediated activation of vα14 NKT cells by glycosylceramides. Science 278: 1626–1629.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Kjer-Nielsen L.,
    2. O. Patel,
    3. A. J. Corbett,
    4. J. Le Nours,
    5. B. Meehan,
    6. L. Liu,
    7. M. Bhati,
    8. Z. Chen,
    9. L. Kostenko,
    10. R. Reantragoon,
    11. et al
    . 2012. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491: 717–723.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Koseki H.,
    2. K. Imai,
    3. T. Ichikawa,
    4. I. Hayata,
    5. M. Taniguchi
    . 1989. Predominant use of a particular α-chain in suppressor T cell hybridomas specific for keyhole limpet hemocyanin. Int. Immunol. 1: 557–564.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Benlagha K.,
    2. A. Weiss,
    3. A. Beavis,
    4. L. Teyton,
    5. A. Bendelac
    . 2000. In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers. J. Exp. Med. 191: 1895–1903.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Matsuda J. L.,
    2. O. V. Naidenko,
    3. L. Gapin,
    4. T. Nakayama,
    5. M. Taniguchi,
    6. C. R. Wang,
    7. Y. Koezuka,
    8. M. Kronenberg
    . 2000. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J. Exp. Med. 192: 741–754.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Lantz O.,
    2. A. Bendelac
    . 1994. 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. 180: 1097–1106.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Porcelli S.,
    2. C. T. Morita,
    3. M. B. Brenner
    . 1992. CD1b restricts the response of human CD4−8− T lymphocytes to a microbial antigen. Nature 360: 593–597.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Exley M.,
    2. J. Garcia,
    3. S. P. Balk,
    4. S. Porcelli
    . 1997. Requirements for CD1d recognition by human invariant Vα24+ CD4−CD8− T cells. J. Exp. Med. 186: 109–120.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Dellabona P.,
    2. G. Casorati,
    3. B. Friedli,
    4. L. Angman,
    5. F. Sallusto,
    6. A. Tunnacliffe,
    7. E. Roosneek,
    8. A. Lanzavecchia
    . 1993. In vivo persistence of expanded clones specific for bacterial antigens within the human T cell receptor alpha/beta CD4−8− subset. J. Exp. Med. 177: 1763–1771.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Tilloy F.,
    2. E. Treiner,
    3. S. H. Park,
    4. C. Garcia,
    5. F. Lemonnier,
    6. H. de la Salle,
    7. A. Bendelac,
    8. M. Bonneville,
    9. O. Lantz
    . 1999. An invariant T cell receptor α chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted α/β T cell subpopulation in mammals. J. Exp. Med. 189: 1907–1921.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Dellabona P.,
    2. E. Padovan,
    3. G. Casorati,
    4. M. Brockhaus,
    5. A. Lanzavecchia
    . 1994. 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. J. Exp. Med. 180: 1171–1176.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Park S. H.,
    2. K. Benlagha,
    3. D. Lee,
    4. E. Balish,
    5. A. Bendelac
    . 2000. Unaltered phenotype, tissue distribution and function of Vα14+ NKT cells in germ-free mice. Eur. J. Immunol. 30: 620–625.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Watarai H.,
    2. E. Sekine-Kondo,
    3. T. Shigeura,
    4. Y. Motomura,
    5. T. Yasuda,
    6. R. Satoh,
    7. H. Yoshida,
    8. M. Kubo,
    9. H. Kawamoto,
    10. H. Koseki,
    11. M. Taniguchi
    . 2012. Development and function of invariant natural killer T cells producing TH2- and TH17-cytokines. PLoS Biol. 10: e1001255.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Lee Y. J.,
    2. K. L. Holzapfel,
    3. J. Zhu,
    4. S. C. Jameson,
    5. K. A. Hogquist
    . 2013. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat. Immunol. 14: 1146–1154.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Dusseaux M.,
    2. E. Martin,
    3. N. Serriari,
    4. I. Péguillet,
    5. V. Premel,
    6. D. Louis,
    7. M. Milder,
    8. L. Le Bourhis,
    9. C. Soudais,
    10. E. Treiner,
    11. O. Lantz
    . 2011. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117: 1250–1259.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Reantragoon R.,
    2. A. J. Corbett,
    3. I. G. Sakala,
    4. N. A. Gherardin,
    5. J. B. Furness,
    6. Z. Chen,
    7. S. B. Eckle,
    8. A. P. Uldrich,
    9. R. W. Birkinshaw,
    10. O. Patel,
    11. et al
    . 2013. Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells. J. Exp. Med. 210: 2305–2320.
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top

In this issue

The Journal of Immunology: 193 (3)
The Journal of Immunology
Vol. 193, Issue 3
1 Aug 2014
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Advertising (PDF)
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about The Journal of Immunology.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
When Less Is More: T Lymphocyte Populations with Restricted Antigen Receptor Diversity
(Your Name) has forwarded a page to you from The Journal of Immunology
(Your Name) thought you would like to see this page from the The Journal of Immunology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
When Less Is More: T Lymphocyte Populations with Restricted Antigen Receptor Diversity
Mitchell Kronenberg
The Journal of Immunology August 1, 2014, 193 (3) 975-976; DOI: 10.4049/jimmunol.1401491

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
When Less Is More: T Lymphocyte Populations with Restricted Antigen Receptor Diversity
Mitchell Kronenberg
The Journal of Immunology August 1, 2014, 193 (3) 975-976; DOI: 10.4049/jimmunol.1401491
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Disclosures
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Conceiving the Inconceivable: The Function of Aire in Immune Tolerance to Peripheral Tissue-Restricted Antigens in the Thymus
  • Glial Cells as Regulators of Neuroimmune Interactions in the Central Nervous System
  • The Colon as a Major Site of Immunoregulation by CD4+ T Cell Subsets in the Steady State
Show more PILLARS OF IMMUNOLOGY

Similar Articles

Navigate

  • Home
  • Current Issue
  • Next in The JI
  • Archive
  • Brief Reviews
  • Pillars of Immunology
  • Translating Immunology

For Authors

  • Submit a Manuscript
  • Instructions for Authors
  • About the Journal
  • Journal Policies
  • Editors

General Information

  • Advertisers
  • Subscribers
  • Rights and Permissions
  • Accessibility Statement
  • Public Access
  • Privacy Policy
  • Disclaimer

Journal Services

  • Email Alerts
  • RSS Feeds
  • ImmunoCasts
  • Twitter

Copyright © 2021 by The American Association of Immunologists, Inc.

Print ISSN 0022-1767        Online ISSN 1550-6606