CD1

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CD1a molecule
Identifiers
Symbol CD1A
Alt. symbolsCD1
NCBI gene 909
HGNC 1634
OMIM 188370
RefSeq NM_001763
UniProt P06126
Other data
Locus Chr. 1 q22-q23
Search for
Structures Swiss-model
Domains InterPro
CD1b molecule
Identifiers
SymbolCD1B
Alt. symbolsCD1
NCBI gene 910
HGNC 1635
OMIM 188360
RefSeq NM_001764
UniProt P29016
Other data
Locus Chr. 1 q22-q23
Search for
Structures Swiss-model
Domains InterPro
CD1c molecule
Identifiers
SymbolCD1C
Alt. symbolsCD1
NCBI gene 911
HGNC 1636
OMIM 188340
RefSeq NM_001765
UniProt P29017
Other data
Locus Chr. 1 q22-q23
Search for
Structures Swiss-model
Domains InterPro
CD1d molecule
Identifiers
Symbol CD1D
NCBI gene 912
HGNC 1637
OMIM 188410
RefSeq NM_001766
UniProt P15813
Other data
Locus Chr. 1 q22-q23
Search for
Structures Swiss-model
Domains InterPro
CD1e molecule
Identifiers
Symbol CD1E
NCBI gene 913
HGNC 1638
OMIM 188411
RefSeq NM_030893
UniProt P15812
Other data
Locus Chr. 1 q22-q23
Search for
Structures Swiss-model
Domains InterPro

CD1 (cluster of differentiation 1) is a family of glycoproteins expressed on the surface of various human antigen-presenting cells. CD1 glycoproteins are structurally related to the class I MHC molecules, however, in contrast to MHC class 1 proteins, they present lipids, glycolipids and small molecules antigens, from both endogenous and pathogenic proteins, to T cells and activate an immune response.

Contents

T cells recognise CD1 using TCR αβ, γδ, [1] [2] [3] or CD36 family members. T cells that are activated by CD1-antigen complexes are called CD1-restricted T cells. [4] 10% of all αβ T lymphocytes in human peripheral blood are Cd1-restricted, out of which, the most abundant are the T cells specific for CD1c. [5]

The human CD1 gene cluster is located on chromosome 1. Genes of the CD1 family were first cloned in 1986, by Franco Calabi and C. Milstein, whereas the first known lipid antigen for CD1 was discovered in 1994, during studies of Mycobacterium tuberculosis . [6] The first antigen that was discovered to be able to bind CD1 and then be recognised by TCR is C80 mycolic acid. Even though their precise function is unknown, The CD1 system of lipid antigen recognition by TCR offers the prospect of discovering new approaches to therapy and developing immunomodulatory agents. [7] [1] [8] [2]

Types

CD1 glycoproteins can be classified primarily into two groups of CD1 isoforms which differ in their lipid anchoring, as well as their expression patterns of the CD1 genes (CD1d is constitutively expressed, whereas the group 1 CD1 genes are inducible and coordinately regulated by myeloid cells). [9]

CD1e is an intermediate form, a soluble lipid transfer protein that is expressed intracellularly. It does not present lipid antigens to T cells, rather plays a role in the processing of lipid antigens and loading them onto other CD1 molecules. [12] [13] [6]

In humans

Group 1

Group 1 CD1 molecules have been shown to present foreign lipid antigens to CD1-specific T cells. Human CD1 cells can recognise and bind a large number of lipids, from monoacylated lipids or lipopeptides to tetra-acylated lipids. However, not all of the lipid ligands can be considered antigens for T-cells. Free fatty acids sphingolipids, phospholipids, sulfolipids, lysophospholipids, amphipathic small molecules and some oils function as natural antigens for T cells. [1] [12]

Group 2

The natural antigens of group 2 CD1 are not well characterized, but a synthetic glycolipid, alpha-galactosylceramide (α-GalCer), originally isolated from a compound found in a marine sponge, has strong biologic activity.

Group 2 CD1 molecules activate a group of T cells, known as natural killer T cells because of their expression of NK surface markers such as CD161. Natural Killer T (NKT) cells are activated by CD1d-presented antigens, and rapidly produce Th1 and Th2 cytokines, typically represented by interferon-gamma and IL-4 production. The group 2 (CD1d) ligand α-GalCer is currently in phase I clinical trials for the treatment of advanced non-hematologic cancers.

NKT cells that respond to α-GalCer are termed "type 1 NKTs". There exists another group of "type 2 NKTs" that do not respond to α-GalCer-CD1D. Instead, they respond to a diverse set of antigens such as sulfatide-CD1d and mycobacterial lipid-CD1d. [3]

Diagnostic relevance

CD1 antigens are expressed on cortical thymocytes, but not on mature T cells. This often remains true in neoplastic cells from these populations, so that the presence of CD1 antigens can be used in diagnostic immunohistochemistry to identify some thymomas and malignancies arising from T cell precursors. CD1a, in particular, is a specific marker for Langerhans cells, and can therefore also be used in the diagnosis of Langerhans cell histiocytosis. Other conditions that may show CD1 positivity include myeloid leukaemia and some B cell lymphomas. [14]

Structure

CD1 proteins consist of a heavy chain with α1, α2, and α3 domains and a transmembrane domain which anchors it to the cell membrane. Much like the MHC molecules, the CD1 heavy chain associates with β2-microglobulin and its binding groove consists of two antiparallel α-helices, placed atop a β-sheet platform. The antigen-binding cleft architecture of CD1 proteins consists of A’, C’, F’ and T’ binding pockets and C’ and D’/E’ accessory portals, which act to accommodate the aliphatic hydrocarbon chains present in lipid, glycolipid, phospholipid, or lipopeptide antigens. CD1 antigen binding clefts are defined by locations of named portals where antigens protrude. [5] [12]

The main difference in structure between MHC and CD1 proteins is that in MHC proteins, the contact region for TCR show lateral symmetry, whereas human CD1 proteins show left-right asymmetry. Another difference between MHC and CD1 proteins is that the antigen display platform of CD1 molecules is smaller than the antigen display groove of MHC molecules. [6]

CD1-lipid TCR interactions

Three models of CD1 recognition by TCR have been described: “head group recognition” model, “absence of interference” model and “altered CD1” model. The “head group recognition” model is considered to be a classical mode of CD1-antigen recognition, whereas the other two models posit that TCR contacts CD1 and not lipid. They are believed to occur in different TCR-antigen-CD1 pairings. [5] [8] [1] [12] The two former models are proven by protein crystallography. [3]

The TCR3d database includes all examples of a CD1-family protein interacting with an TCR in the Protein Data Bank, updated periodically.

CD36 interactions

Although it is known that CD1 binds to CD36, there is currently (as of January 2026) no structual characterization of the nature of the interaction.

In other animals

Rodents

Mice lack the group 1 CD1 molecules, and instead have 2 copies of CD1d. Thus, mice have been used extensively to characterize the role of CD1d and CD1d-dependent NKT cells in a variety of disease models. Rats also lack group 1 CD1 molecules.

Guinea pigs have both groups of CD1 and are commonly used as the alternative model animal for CD1 research. [15] Specifically, they express four orthologs of the group 1 CD1b protein and three orthologs of CD1c, as well as one ortholog of CD1d. [16]

Ruminants

Cows have one copy each of CD1a and CD1e, several copies of CD1b, and no copies of CD1c. [17] Ruminants including cows were previously thought to have no functional copies of CD1d (only pseudogenes) due to lack of reaction to αGalCer when tested using mouse iNKT cells, but later research has shown CD1d to be expressed and the genes for the NKT machinery to be present. It turns out bovine CD1d has an altered binding pocket causing a different binding "pose". The change also incurs a limit on the length of the glycosphingolipid antigen. [18]

Because of the fact that cows are a natural host of Mycobacterium bovis , a pathogen in humans as well, it is hoped that studying cows will yield insights into the group 1 CD1 antigen-presenting system. M. bovis is also very similar to M. tuberculosis genetically. Cows are a valuable model organism for studying immune responses to tuberculosis with many similarities to humans. Nevertheless, they have their own special features such as the aforementioned CD1 repertoire and a special division of labor among δγ T cells by expression of WC1, a protein not found in primates. [19]

References

  1. 1 2 3 4 Layre E, de Jong A, Moody DB (December 2014). "Human T cells use CD1 and MR1 to recognize lipids and small molecules". Current Opinion in Chemical Biology. Molecular immunology. 23: 31–38. doi:10.1016/j.cbpa.2014.09.007. PMID   25271021.
  2. 1 2 3 Tang Y, Ma S, Lin S, Wu Y, Chen S, Liu G, Ma L, Wang Z, Jiang L, Wang Y (2023-03-01). "Cell-free protein synthesis of CD1E and B2M protein and in vitro interaction" . Protein Expression and Purification. 203 106209. doi:10.1016/j.pep.2022.106209. ISSN   1046-5928. PMID   36460227. S2CID   254180046.
  3. 1 2 3 4 Cao TP, Shahine A, Cox LR, Besra GS, Moody DB, Rossjohn J (August 2024). "A structural perspective of how T cell receptors recognize the CD1 family of lipid antigen-presenting molecules". The Journal of Biological Chemistry. 300 (8): 107511. doi: 10.1016/j.jbc.2024.107511 . PMC   11780374 . PMID   38945451.{{cite journal}}: CS1 maint: article number as page number (link)
  4. ↑ Gherardin NA, Redmond SJ, McWilliam HE, Almeida CF, Gourley KH, Seneviratna R, Li S, De Rose R, Ross FJ, Nguyen-Robertson CV, Su S, Ritchie ME, Villadangos JA, Moody DB, Pellicci DG, Uldrich AP, Godfrey DI (15 June 2021). "CD36 family members are TCR-independent ligands for CD1 antigen–presenting molecules". Science Immunology. 6 (60) eabg4176. doi:10.1126/sciimmunol.abg4176. PMC   8418821 . PMID   34172588.
  5. 1 2 3 4 5 6 Moody DB, Cotton RN (2017-06-01). "Four pathways of CD1 antigen presentation to T cells". Current Opinion in Immunology. Antigen processing * Special section: Metabolism of T cells. 46: 127–133. doi:10.1016/j.coi.2017.07.013. ISSN   0952-7915. PMC   5599164 . PMID   28756303.
  6. 1 2 3 4 Van Rhijn I, Godfrey DI, Rossjohn J, Moody DB (October 2015). "Lipid and small-molecule display by CD1 and MR1". Nature Reviews. Immunology. 15 (10): 643–654. doi:10.1038/nri3889. PMC   6944187 . PMID   26388332.
  7. ↑ Porcelli S, Brenner MB, Greenstein JL, Balk SP, Terhorst C, Bleicher PA (October 1989). "Recognition of cluster of differentiation 1 antigens by human CD4-CD8-cytolytic T lymphocytes". Nature. 341 (6241): 447–450. Bibcode:1989Natur.341..447P. doi:10.1038/341447a0. PMID   2477705. S2CID   4264602.
  8. 1 2 3 4 5 Moody DB, Suliman S (2017-10-30). "CD1: From Molecules to Diseases". F1000Research. 6: 1909. doi: 10.12688/f1000research.12178.1 . PMC   5664979 . PMID   29152228.
  9. ↑ Zajonc DM, Wilson IA (2007). "Architecture of CD1 Proteins". T Cell Activation by CD1 and Lipid Antigens. Current Topics in Microbiology and Immunology. Vol. 314. pp. 27–50. doi:10.1007/978-3-540-69511-0_2. ISBN   978-3-540-69510-3. PMID   17593656.
  10. ↑ Sköld M, Behar SM (March 2005). "The role of group 1 and group 2 CD1-restricted T cells in microbial immunity". Microbes and Infection. 7 (3): 544–551. doi: 10.1016/j.micinf.2004.12.012 . PMID   15777730.
  11. ↑ Mori L, Lepore M, De Libero G (2016-05-20). "The Immunology of CD1- and MR1-Restricted T Cells" . Annual Review of Immunology. 34 (1): 479–510. doi:10.1146/annurev-immunol-032414-112008. ISSN   0732-0582. PMID   26927205.
  12. 1 2 3 4 Zajonc DM (August 2016). "The CD1 family: serving lipid antigens to T cells since the Mesozoic era". Immunogenetics. 68 (8): 561–576. doi:10.1007/s00251-016-0931-0. ISSN   0093-7711. PMC   5087154 . PMID   27368414.
  13. ↑ Angenieux C, Salamero J, Fricker D, Cazenave JP, Goud B, Hanau D, de La Salle H (December 2000). "Characterization of CD1e, a third type of CD1 molecule expressed in dendritic cells". The Journal of Biological Chemistry. 275 (48): 37757–37764. doi: 10.1074/jbc.M007082200 . PMID   10948205.
  14. ↑ Kumarasen C, Anthony S-Y L (2003). Manual of diagnostic antibodies for immunohistology. London: Greenwich Medical Media. pp. 59–60. ISBN   1-84110-100-1.
  15. ↑ Milton M, Mansour S (2025). "CD1-restricted T cells: are unconventional allies the key to future TB vaccines?". Frontiers in Immunology. 16 1629466. doi: 10.3389/fimmu.2025.1629466 . PMC   12286804 . PMID   40709176.
  16. ↑ Harris MC, Gary HE, Cooper SK, Ackart DF, DiLisio JE, Basaraba RJ, Cheng TY, van Rhijn I, Branch Moody D, Podell BK (10 December 2024). "Establishment of CD1b-restricted immunity to lipid antigens in the pulmonary response to Mycobacterium tuberculosis infection". Infection and Immunity. 92 (12): e0038024. doi:10.1128/iai.00380-24. PMC   11629625 . PMID   39494875.
  17. ↑ Van Rhijn I, Koets AP, Im JS, Piebes D, Reddington F, Besra GS, et al. (April 2006). "The bovine CD1 family contains group 1 CD1 proteins, but no functional CD1d". Journal of Immunology. 176 (8): 4888–4893. doi: 10.4049/jimmunol.176.8.4888 . PMID   16585584.
  18. ↑ Wang J, Guillaume J, Pauwels N, Van Calenbergh S, Van Rhijn I, Zajonc DM (2012). "Crystal structures of bovine CD1d reveal altered αGalCer presentation and a restricted A' pocket unable to bind long-chain glycolipids". PLOS ONE. 7 (10): e47989. Bibcode:2012PLoSO...747989W. doi: 10.1371/journal.pone.0047989 . PMC   3479135 . PMID   23110152.{{cite journal}}: CS1 maint: article number as page number (link)
  19. ↑ Waters WR, Palmer MV, Thacker TC, Davis WC, Sreevatsan S, Coussens P, Meade KG, Hope JC, Estes DM (2011). "Tuberculosis immunity: opportunities from studies with cattle". Clinical & Developmental Immunology. 2011: 768542. doi: 10.1155/2011/768542 . PMC   3004413 . PMID   21197095.{{cite journal}}: CS1 maint: article number as page number (link)
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