The burgeoning family of unconventional T cells

Journal name:
Nature Immunology
Year published:
Published online
Corrected online


While most studies of T lymphocytes have focused on T cells reactive to complexes of peptide and major histocompatibility complex (MHC) proteins, many other types of T cells do not fit this paradigm. These include CD1-restricted T cells, MR1-restricted mucosal associated invariant T cells (MAIT cells), MHC class Ib–reactive T cells, and γδ T cells. Collectively, these T cells are considered 'unconventional', in part because they can recognize lipids, small-molecule metabolites and specially modified peptides. Unlike MHC-reactive T cells, these apparently disparate T cell types generally show simplified patterns of T cell antigen receptor (TCR) expression, rapid effector responses and 'public' antigen specificities. Here we review evidence showing that unconventional T cells are an abundant component of the human immune system and discuss the immunotherapeutic potential of these cells and their antigenic targets.

At a glance


  1. Comparison of unconventional and MHC-restricted T cell responses.
    Figure 1: Comparison of unconventional and MHC-restricted T cell responses.

    The left half of the graph represents initial infection and the right half a recall response (a memory response); the dashed line denotes re-infection. In general, the key differences in the patterns of MHC-restricted T cells and unconventional T cells relate to the initial number of antigen-specific populations, the timing of the response, the role of memory T cells and the extent to which individuals in an outbred population respond to the same kinds of antigens. See Table 1 for further details of the two types of T cell responses.

  2. Unconventional [alpha][beta] T cell populations.
    Figure 2: Unconventional αβ T cell populations.

    Interactions of unconventional αβ T cells with their antigen targets via their TCRs in human cells (a) and mouse cells (b). Different antigen-presenting cell types can vary in their expression of antigen-presenting molecules. β2m, β2-microglobulin; CMV, cytomegalovirus; iGb3, isoglobotrihexosylceramide; Ag, antigen.

  3. Populations of [gamma][delta] T cells.
    Figure 3: Populations of γδ T cells.

    Different types of γδ T cells interact in various ways with their antigen targets via their TCRs, as shown for human γδ T cells (a) and mouse γδ T cells (b). Different antigen-presenting cell types can vary in their expression of antigen-presenting molecules. Cy3, indocarbocyanine.

  4. Frequency of some antigen-specific T cell types.
    Figure 4: Frequency of some antigen-specific T cell types.

    Approximate frequency (per 1 × 106 T cells) of MAIT cells (from refs. 75,76), type I NKT cells (from refs. 158,159), CD1a- and CD1c-reactive T cells (from refs. 54,64), TRDV2+TRGV9+ γδ T cells (from ref.110), and a small selection of peptide-MHC–specific T cells (from ref. 3) in humans (left) or mice (right); where numbers vary among reports, a conservative estimate is presented. Antigen specificities (horizontal axis): BTN3A1, butyrophilin 3A1; HIV Gag77, human immunodeficiency virus group-specific antigen (amino acids 77–85); HCV NS3 1073, hepatitis C virus nonstructural protein 3 (amino acids 1073–1081); CMV-pp65-495, cytomegalovirus polyprotein 65 (amino acids 495–503); B. anthracis, Bacillus anthracis; PA713, protective antigen (amino acids 713–732); PA401, protective antigen (amino acids 401–420); PA713, protective antigen (amino acids 713–732); OVA257, ovalbumin peptide (amino acids 257–264); LCMV gp33, lymphocytic choriomeningitis virus glycoprotein (amino acids 33–41); MHV M133, mouse hepatitis virus M protein (amino acids 133–147); OVA329, ovalbumin peptide (amino acids 329–337); 2W, peptide from I-E (amino acids 52–68).

  5. Antigens detected by unconventional [alpha][beta] T cells.
    Figure 5: Antigens detected by unconventional αβ T cells.

    Structures of antigens for CD1 and MR1 antigen-presenting molecules. a-GlcCer, α-glucosylceramide; α-GalDAG, α-galactosyldiacylglycerol; HC3-methyl-PPBF, 3-methyl PPBF; 5-OE-RU, 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU); RL-6-Me-7-OH, 7-hydroxy-6-methyl-8-D-ribityllumazine; RL-6,7-diMe 6,7-dimethyl-8-D-ribityllumazine.

Change history

Corrected online 13 November 2015
In the version of this article initially published, the vertical axes of Figure 4 were labeled incorrectly as "(per 1 × 105 T cells)." The correct label is "(per 1 × 106 T cells)." These errors have been corrected for the PDF and HTML versions of this article.


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Author information


  1. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia.

    • Dale I Godfrey,
    • Adam P Uldrich &
    • James McCluskey
  2. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, University of Melbourne, Parkville, Australia.

    • Dale I Godfrey &
    • Adam P Uldrich
  3. Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.

    • Jamie Rossjohn
  4. Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.

    • Jamie Rossjohn
  5. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia.

    • Jamie Rossjohn
  6. Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • D Branch Moody

Competing financial interests

D.I.G. is chair of the scientific advisory panel for Avalia Immunotherapies.

Corresponding author

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Supplementary information

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  1. Supplementary Table 1 (93 KB)

    Characteristics of non-conventional T cells

Additional data