Mol. Cells

Current Understanding of the Roles of CD1a-Restricted T Cells in the Immune System

Hyun Jung Yoo, Na Young Kim, and Ji Hyung Kim

Additional article information


Cluster of differentiation 1 (CD1) is a family of cell-surface glycoproteins that present lipid antigens to T cells. Humans have five CD1 isoforms. CD1a is distinguished by the small volume of its antigen-binding groove and its stunted A′ pocket, its high and exclusive expression on Langerhans cells, and its localization in the early endosomal and recycling intracellular trafficking compartments. Its ligands originate from self or foreign sources. There are three modes by which the T-cell receptors of CD1a-restricted T cells interact with the CD1a:lipid complex: they bind to both the CD1a surface and the antigen or to only CD1a itself, which activates the T cell, or they are unable to bind because of bulky motifs protruding from the antigen-binding groove, which might inhibit autoreactive T-cell activation. Recently, several studies have shown that by producing TH2 or TH17 cytokines, CD1a-restricted T cells contribute to inflammatory skin disorders, including atopic dermatitis, psoriasis, allergic contact dermatitis, and wasp/bee venom allergy. They may also participate in other diseases, including pulmonary disorders and cancer, because CD1a-expressing dendritic cells are also located in non-skin tissues. In this mini-review, we discuss the current knowledge regarding the biology of CD1a-reactive T cells and their potential roles in disease.

Keywords: CD1 molecules, CD1a, inflammatory skin diseases, lipid antigens, lipid-reactive T cells


Research over the last few decades has greatly advanced our knowledge about major histocompatibility complex (MHC)-restricted T cells. The widely held notion that T cells recognize MHC molecules complexed with peptide antigens has now been supplanted by the understanding that T cells can recognize a much broader range of antigens, including carbohydrates (Carbone and Gleeson, 1997), metals (Gamerdinger et al., 2003), small metabolites (Corbett et al., 2014; Kjer-Nielsen et al., 2012), and lipids (Beckman et al., 1994; Kawano et al., 1997). With regard to the latter, multiple studies have shown that T cells can recognize lipid antigens that are complexed to MHC-like proteins called cluster of differentiation 1 (CD1) (Porcelli et al., 1989). The human CD1 family contains five isoforms designated CD1a to CD1e that differ in their antigen-binding groove properties, intracellular-trafficking routes, and cell/tissue expression; consequently, they present different lipid-antigen repertoires. Since mice bear only CD1d (Park et al., 2001), CD1d-restricted T cells are well understood. However, the immunological roles of the other human isoforms are less well understood, including CD1a, the focus of this review.

Lipid-reactive T cells play crucial roles in the pathogenesis of certain diseases, including autoimmune (Akbari et al., 2003; Kim et al., 2016) and infectious diseases (Kinjo et al., 2006; Raftery et al., 2008) and cancer (Lepore et al., 2014). In particular, CD1a-reactive T cells are the most frequent CD1-restricted T cells in the blood and participate in the immune response to bacterial infection (Rosat et al., 1999; Visvabharathy et al., 2020) and might play important roles in asthma (Bertorelli et al., 2000), allergy (Agea et al., 2005), psoriasis (Kim et al., 2016), and allergic contact dermatis (ACD) (Betts et al., 2017) immunopathogenesis.

Here, we summarize the molecular properties of the CD1 isoforms, their lipid antigens, and CD1-restricted T cells, with particular focus on CD1a. We then discuss the roles that CD1a-reactive T cells play in several diseases.


The CD1 isoforms in human

The CD1 molecules are structurally related to MHC I and like them, present antigen to αβ and γδ T cells (Zeng et al., 1997). However, the antigens originate from lipids, not proteins. All placental mammals have CD1 genes. They are highly conserved and show limited allelic polymorphism (Han et al., 1999; Seshadri et al., 2013), unlike the MHC I and II molecules, which are extremely polymorphic and bear dozens to hundreds of allelic variants (Radwan et al., 2020). The five CD1 isoforms in humans fall into three groups on the basis of sequence homology and immune functions (Angenieux et al., 2000; Calabi et al., 1989). Thus, group 1 contains CD1a, CD1b, and CD1c, which present antigens to clonally diverse T cells. Group 2 contains CD1d, which mostly presents antigens to invariant natural killer T (iNKT) cells. Group 3 contains CD1e, which acts as a lipid chaperone for other CD1 isoforms rather than an antigen presenting molecule (Facciotti et al., 2011).

The CD1a isoform

The structure of CD1a

The CD1a proteins consist of a heavy chain with three extracellular domains (α1, α2, and α3), a transmembrane domain, and a short cytoplasmic tail that is non-covalently associated with the β2-microglobulin light chain (Zeng et al., 1997). The α1 and α2 domains form the antigen-binding groove (Fig. 1) (Zajonc et al., 2003). The CD1a antigen-binding groove is narrow and deep and bears non-polar amino acids (Zajonc et al., 2003). These groove characteristics are particularly suited to binding lipids and are evolutionarily conserved (Gadola et al., 2002; Scharf et al., 2010; Zajonc et al., 2003; Zeng et al., 1997). The groove bears two pockets, A′ and F′. A′ is longer and narrower than F′ and is overlaid with a roof-like structure that separates it from the outer protein surface (Fig. 1) (Zajonc et al., 2003). F′ connects A′ to the outer surface and lies close to the T-cell receptor (TCR) recognition region (Zajonc et al., 2003). In more detail, its A′ pocket has a fixed terminus that restricts the length of the inserted alkyl chain (Zajonc et al., 2003). F′ also bears residues that can form hydrogen bonds with the peptide moiety of an antigen (Zajonc et al., 2005). These A′ and F′ features explain how CD1a bind amphipathic lipid antigens, namely, they bear an aliphatic moiety that is deeply buried in A′ and is sequestered from the surrounding aqueous solvent while the polar head-group of the antigen (e.g., carbohydrate, phosphate, peptidic, or other hydrophilic moieties) can protrude from F′ for TCR recognition (Zajonc et al., 2003; 2005).

CD1a assembly and intracellular trafficking
Figure F1
(A) The structural feature of CD1a. The heavy chain consists of three domains (α1, α2, α3) with a short cytoplasmic tail, and it is non-covalently associated with a light chain ...

The antigen repertoires of the CD1 isoforms are further shaped by their disparate intracellular-trafficking routes, which exposes them to different antigen arrays. Thus, newly synthesized CD1 heavy chains in the endoplasmic reticulum lumen assemble with β2-microglobulin light chains and spacer ligands (Sugita et al., 1997). The CD1s then leave the Golgi and travel to the plasma membrane. The route the isoforms then take differs: CD1a goes directly to sorting and recycling endosomes and predominantly localizes at the cell surface (Barral et al., 2008; Sugita et al., 1999), and other CD1 isoforms enter late endosomal or lysosomal compartments (Briken et al., 2000; Sugita et al., 1999; 2000). This is because the cytoplasmic tails of other isoforms bear tyrosine-based motifs to which adaptor protein-2 or -3 binds (Briken et al., 2002; Sugita et al., 2002). However, CD1a lacks known endosomal sorting motifs and is internalized from the plasma membrane into early endosomes by an adaptor protein-independent pathway. The effect of these different intracellular trafficking mechanisms on the antigen repertoires of the CD1 isoforms is exhibited by the case of sulfatide: even though all group 1 CD1s can present this promiscuous glycolipid in vitro (Shamshiev et al., 2002), in vivo it is very largely presented by CD1a due to its co-localization in early endosomes (Cernadas et al., 2010). Notably, the endogenous ligand in the CD1a antigen-binding groove is easily replaced by exogenous lipids and those that do not require intracellular-antigen processing; this process can happen at the cell surface and may in fact stabilize/upregulate cell-surface CD1a expression (Manolova et al., 2006). This type of antigen loading is also observed with other CD1 isoforms but is more common with CD1a. These CD1a features suggest that its antigen repertoire may better reflect the extracellular lipid milieu than those of the other isoforms (Manolova et al., 2006).

CD1a tissue- and cell-specific expression

CD1a is further distinguished from the other CD1s by being constitutively and highly expressed on Langerhans cells and antigen presenting cell (APC) subsets in the skin (Wollenberg et al., 1996). It is also expressed by DCs in mucosal tissues, including the bronchus (Tazi et al., 1993), conjunctiva (Yoshida et al., 1997), cervix (Miller et al., 1992), and lungs (Baharom et al., 2016; Haniffa et al., 2012).

Antigens of CD1a

CD1a presents a diverse array of self and foreign lipids. Many of its self-lipids are small and very hydrophobic lipids such as wax ester, triacylglyceride, squalene (de Jong et al., 2014), and farnesol (Nicolai et al., 2020). While most CD1a self-antigens are lipid metabolites that bind to CD1a in endosomes, CD1a can also bind free fatty acid neoantigens that are, for example, generated from common cell membrane phosphodiacylglycerides by wasp and bee venom phospholipase A2 (PLA2) and then bind to CD1a in the extracellular space (Bourgeois et al., 2015). The CD1a-binding foreign antigens include the lipopeptide didehydroxymycobactin (DDM), which scavenges iron, thereby promoting Mycobacterium tuberculosis growth within macrophages (Moody et al., 2004). Thus, CD1a presents a broad array of lipid antigens; this makes it a highly versatile mediator of many different immune responses.

Modes by which T cells interact with CD1a

The second and third CD1a:T cell interaction modes are less antigen-specific, sometimes even antigen-independent (de Jong et al., 2014; Sieling et al., 2005). The second mode is called “absence of interference” (de Jong et al., 2014):some CD1a-restricted T cells recognize small highly hydrophobic permissive headless lipids (Birkinshaw et al., 2015; de Jong et al., 2014; Nicolai et al., 2020) that are completely buried inside CD1a and allow the TCR to bind to the roof over A′ (Birkinshaw et al., 2015). Thus, the TCR does not directly contact the antigen or require its specific positioning (de Jong et al., 2014). Mutation of the A′ roof generally blocks “absence of interference” recognition (Cotton et al., 2021). The third mode is mediated by certain non-permissive lipids whose polar head-groups block TCR:CD1a interaction, thereby inhibiting autoreactive T-cell activation (Birkinshaw et al., 2015; de Jong et al., 2014). It may be a regulatory mechanism that blocks autoimmune reactions in non-inflammatory conditions to the abundant lipid antigens being presented by CD1a-expressing APCs.


The αβ TCRs of CD1a-restricted T cells are probably as variable as those of conventional αβ T cells: de Jong et al. (2010) showed that while some CD1a-restricted T cell clones have the same variable or joining regions, most have different CDR3 sequences. This variability was also observed for T cells from the same donor (Cotton et al., 2021; de Lalla et al., 2011).

A cell-surface marker/cytokine phenotype that identifies all CD1a-restricted T cells is not yet available. However, several CD1a-restricted T-cell subset phenotypes have been reported. They include skin-homing TH22 cells in the blood that express cutaneous lymphocyte antigen, CCR4, CCR6, and CCR10 and secrete interleukin (IL)-22 (de Jong et al., 2010). CD1a-restricted TH1, TH2, and TH17 subsets also participate in various diseases (Jarrett et al., 2016; Kim et al., 2016; Subramaniam et al., 2016). The different cytokine profiles of CD1a-restricted T cells suggest that they may function in multiple different ways in the immune system.

CD1a-restricted T cells are often detected by measuring their production of specific cytokines in the presence and absence of anti-CD1a blocking antibody. This method can overlook inactive CD1a-restricted T cells and T cells that produce non-targeted cytokines. This can be overcome by CD1a-tetramer staining. CD1d-tetramer staining has greatly facilitated the identification/characterization of CD1d-restricted T cells (Benlagha et al., 2000; Matsuda et al., 2000). Studies show that CD1a tetramers can detect CD1a-restricted T cells, including DDM-specific (Kasmar et al., 2013) and Jurkat.BK6 CD1a-restricted T cells (Birkinshaw et al., 2015). Unloaded CD1a-tetramers (i.e., endogenous lipid:CD1a complexes) also identify CD1a-autoreactive T cells in human skin (Cotton et al., 2021). Thus, the tetramer method will provide new insights into CD1a-restricted T cells, including their frequencies in different organs and their cytokine profiles, TCR patterns, and novel markers. This in turn may reveal multiple subsets with different functions and will yield a more fine-tuned classification system for these T cells.


Skin diseases

CD1a is abundantly expressed in the skin and the blood contains large numbers of skin-homing CD1a-restricted T cells (de Jong et al., 2010). This suggests that CD1a-restricted T cells may participate in skin diseases. Indeed, there are several CD1a-mediated skin diseases, which can be grouped according to whether self-antigens or foreign antigens drive the pathological process.

Skin diseases mediated by self-antigens

Wasp/bee venom allergy associates with cutaneous inflammation and in the worst cases with systemic allergic responses such as anaphylactic shock and death. Patients with wasp/bee venom allergy have higher frequencies of TH2-biased CD1a-restricted T cells that express IL-13 and promote IgE production. Notably, when patients gained clinical tolerance to wasp/bee venom via subcutaneous immunotherapy, their peripheral blood CD1a-restricted T cells lost their TH2 responses (Subramaniam et al., 2016).

Skin diseases mediated by foreign antigens

Thus, this overview of CD1a-related skin diseases suggests that novel therapeutic targets for treating skin diseases may include CD1a-restricted T cells, PLA2, and CD1a molecules.

Non-skin diseases

Since CD1a is expressed in tissues other than skin, CD1a-restricted T cells may also play pathological roles in non-skin diseases, including asthma and allergy: thus, human lung DCs express CD1a (Baharom et al., 2016; Haniffa et al., 2012); atopic asthma patients have greater numbers of CD1a+ cells in the airway (Bertorelli et al., 2000); and patients who are allergic to cypress pollens have CD1a-restricted responses to these antigens in their peripheral blood (Agea et al., 2005). Notably, the lipophilic air pollutant benzo[a]pyrene, which associates with cardiovascular, lung, and autoimmune diseases, has been shown to decrease CD1a surface expression, thereby reducing CD1a-restricted T-cell activation in human (Sharma et al., 2017).

Tumor microenvironments may modulate CD1a expression, thereby shaping CD1a-restricted T cell anti-tumor activities. In gallbladder cancer, patients with marked CD1a+ DC infiltration into the tumor survived longer and were less likely to develop distant metastasis than patients with low CD1a+ DC infiltration (Kai et al., 2021). However, this prognostic relationship was not observed in early breast cancer patients (Schnellhardt et al., 2020) and studies on colorectal cancer patients showed that high CD1a+ DC numbers in advancing tumor margins associated with shorter disease-free survival (Sandel et al., 2005; Suzuki et al., 2002). The clinical relevance of CD1a+ DCs in tumors, the tumor-derived antigens that drive CD1a-restricted T cells, how tumor microenvironments regulate CD1a, and how CD1a-restricted T cells affect tumor growth remain to be clarified.


Here, we reviewed current knowledge about CD1a, CD1a-restricted T cells, and their pathological roles (Fig. 2). Through this review, we emphasized mechanisms of antigen-processing by CD1a, activation modes of CD1a-restricted T cells, and their roles in immune disorders such as contact dermatitis, atopic dermatitis, and psoriasis. We also pointed out the limitations of previous studies and questions unsolved, including the development, naïve-to-effector/memory dynamics, and subpopulations of CD1a-restricted T cells and their potential roles in non-skin diseases. Studies using human CD1 transgenic mice or other experimental animal models may help elucidate the CD1a and CD1a-reactive T cells functions in the immune system.

Figure F2
CD1a-expressing APCs are abundant, but not limited, in skin. Antigens of CD1a are derived from self or various foreign sources such as Mycobacteria, plants and cosmetics, and presented on CD1a ...

Article information

Mol. Cells.May 31, 2021; 44(5): 310-317.
Published online 2021-05-12. doi:  10.14348/molcells.2021.0059
1Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
Received March 14, 2021; Accepted April 1, 2021.
Articles from Mol. Cells are provided here courtesy of Mol. Cells


  • Agea, E., Russano, A., Bistoni, O., Mannucci, R., Nicoletti, I., Corazzi, L., Postle, A.D., De Libero, G., Porcelli, S.A., and Spinozzi, F. (2005). Human CD1-restricted T cell recognition of lipids from pollens. J. Exp. Med.. 202, 295-308.
  • Akbari, O., Stock, P., Meyer, E., Kronenberg, M., Sidobre, S., Nakayama, T., Taniguchi, M., Grusby, M.J., DeKruyff, R.H., and Umetsu, D.T. (2003). Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat. Med.. 9, 582-588.
  • Angenieux, C., Salamero, J., Fricker, D., Cazenave, J.P., Goud, B., Hanau, D., and de La Salle, H. (2000). Characterization of CD1e, a third type of CD1 molecule expressed in dendritic cells. J. Biol. Chem.. 275, 37757-37764.
  • Baharom, F., Thomas, S., Rankin, G., Lepzien, R., Pourazar, J., Behndig, A.F., Ahlm, C., Blomberg, A., and Smed-Sorensen, A. (2016). Dendritic cells and monocytes with distinct inflammatory responses reside in lung mucosa of healthy humans. J. Immunol.. 196, 4498-4509.
  • Balato, A., Lembo, S., Mattii, M., Schiattarella, M., Marino, R., De Paulis, A., Balato, N., and Ayala, F. (2012). IL-33 is secreted by psoriatic keratinocytes and induces pro-inflammatory cytokines via keratinocyte and mast cell activation. Exp. Dermatol.. 21, 892-894.
  • Barral, D.C., Cavallari, M., McCormick, P.J., Garg, S., Magee, A.I., Bonifacino, J.S., De Libero, G., and Brenner, M.B. (2008). CD1a and MHC class I follow a similar endocytic recycling pathway. Traffic. 9, 1446-1457.
  • Beckman, E.M., Porcelli, S.A., Morita, C.T., Behar, S.M., Furlong, S.T., and Brenner, M.B. (1994). Recognition of a lipid antigen by CD1-restricted αβ+ T cells. Nature. 372, 691-694.
  • Benlagha, K., Weiss, A., Beavis, A., Teyton, L., and Bendelac, A. (2000). In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers. J. Exp. Med.. 191, 1895-1903.
  • Bertorelli, G., Bocchino, V., Zhou, X., Zanini, A., Bernini, M.V., Damia, R., Di Comite, V., Grima, P., and Olivieri, D. (2000). Dendritic cell number is related to IL-4 expression in the airways of atopic asthmatic subjects. Allergy. 55, 449-454.
  • Betts, R.J., Perkovic, A., Mahapatra, S., Del Bufalo, A., Camara, K., Howell, A.R., Martinozzi Teissier, S., De Libero, G., and Mori, L. (2017). Contact sensitizers trigger human CD1-autoreactive T-cell responses. Eur. J. Immunol.. 47, 1171-1180.
  • Birkinshaw, R.W., Pellicci, D.G., Cheng, T.Y., Keller, A.N., Sandoval-Romero, M., Gras, S., de Jong, A., Uldrich, A.P., Moody, D.B., and Godfrey, D.I. (2015). αβ T cell antigen receptor recognition of CD1a presenting self lipid ligands. Nat. Immunol.. 16, 258-266.
  • Bourgeois, E.A., Subramaniam, S., Cheng, T.Y., De Jong, A., Layre, E., Ly, D., Salimi, M., Legaspi, A., Modlin, R.L., and Salio, M. (2015). Bee venom processes human skin lipids for presentation by CD1a. J. Exp. Med.. 212, 149-163.
  • Briken, V., Jackman, R.M., Dasgupta, S., Hoening, S., and Porcelli, S.A. (2002). Intracellular trafficking pathway of newly synthesized CD1b molecules. EMBO J.. 21, 825-834.
  • Briken, V., Jackman, R.M., Watts, G.F., Rogers, R.A., and Porcelli, S.A. (2000). Human CD1b and CD1c isoforms survey different intracellular compartments for the presentation of microbial lipid antigens. J. Exp. Med.. 192, 281-288.
  • Calabi, F., Jarvis, J.M., Martin, L., and Milstein, C. (1989). Two classes of CD1 genes. Eur. J. Immunol.. 19, 285-292.
  • Carbone, F.R. and Gleeson, P.A. (1997). Carbohydrates and antigen recognition by T cells. Glycobiology. 7, 725-730.
  • Cernadas, M., Cavallari, M., Watts, G., Mori, L., De Libero, G., and Brenner, M.B. (2010). Early recycling compartment trafficking of CD1a is essential for its intersection and presentation of lipid antigens. J. Immunol.. 184, 1235-1241.
  • Cheung, K.L., Jarrett, R., Subramaniam, S., Salimi, M., Gutowska-Owsiak, D., Chen, Y.L., Hardman, C., Xue, L., Cerundolo, V., and Ogg, G. (2016). Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a. J. Exp. Med.. 213, 2399-2412.
  • Corbett, A.J., Eckle, S.B., Birkinshaw, R.W., Liu, L., Patel, O., Mahony, J., Chen, Z., Reantragoon, R., Meehan, B., and Cao, H. (2014). T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature. 509, 361-365.
  • Cotton, R.N., Cheng, T.Y., Wegrecki, M., Le Nours, J., Orgill, D.P., Pomahac, B., Talbot, S.G., Willis, R.A., Altman, J.D., and de Jong, A. (2021). Human skin is colonized by T cells that recognize CD1a independently of lipid. J. Clin. Invest.. 131, e140706.
  • de Jong, A., Cheng, T.Y., Huang, S., Gras, S., Birkinshaw, R.W., Kasmar, A.G., Van Rhijn, I., Pena-Cruz, V., Ruan, D.T., and Altman, J.D. (2014). CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens. Nat. Immunol.. 15, 177-185.
  • de Jong, A., Pena-Cruz, V., Cheng, T.Y., Clark, R.A., Van Rhijn, I., and Moody, D.B. (2010). CD1a-autoreactive T cells are a normal component of the human αβ T cell repertoire. Nat. Immunol.. 11, 1102-1109.
  • de Lalla, C., Lepore, M., Piccolo, F.M., Rinaldi, A., Scelfo, A., Garavaglia, C., Mori, L., De Libero, G., Dellabona, P., and Casorati, G. (2011). High-frequency and adaptive-like dynamics of human CD1 self-reactive T cells. Eur. J. Immunol.. 41, 602-610.
  • Facciotti, F., Cavallari, M., Angenieux, C., Garcia-Alles, L.F., Signorino-Gelo, F., Angman, L., Gilleron, M., Prandi, J., Puzo, G., and Panza, L. (2011). Fine tuning by human CD1e of lipid-specific immune responses. Proc. Natl. Acad. Sci. U. S. A.. 108, 14228-14233.
  • Gadola, S.D., Zaccai, N.R., Harlos, K., Shepherd, D., Castro-Palomino, J.C., Ritter, G., Schmidt, R.R., Jones, E.Y., and Cerundolo, V. (2002). Structure of human CD1b with bound ligands at 2.3 Å, a maze for alkyl chains. Nat. Immunol.. 3, 721-726.
  • Gamerdinger, K., Moulon, C., Karp, D.R., Van Bergen, J., Koning, F., Wild, D., Pflugfelder, U., and Weltzien, H.U. (2003). A new type of metal recognition by human T cells: contact residues for peptide-independent bridging of T cell receptor and major histocompatibility complex by nickel. J. Exp. Med.. 197, 1345-1353.
  • Han, M., Hannick, L.I., DiBrino, M., and Robinson, M.A. (1999). Polymorphism of human CD1 genes. Tissue Antigens. 54, 122-127.
  • Haniffa, M., Shin, A., Bigley, V., McGovern, N., Teo, P., See, P., Wasan, P.S., Wang, X.N., Malinarich, F., and Malleret, B. (2012). Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity. 37, 60-73.
  • Hardman, C.S., Chen, Y.L., Salimi, M., Jarrett, R., Johnson, D., Jarvinen, V.J., Owens, R.J., Repapi, E., Cousins, D.J., and Barlow, J.L. (2017). CD1a presentation of endogenous antigens by group 2 innate lymphoid cells. Sci. Immunol.. 2, eaan5918.
  • Jarrett, R., Salio, M., Lloyd-Lavery, A., Subramaniam, S., Bourgeois, E., Archer, C., Cheung, K.L., Hardman, C., Chandler, D., and Salimi, M. (2016). Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase. Sci. Transl. Med.. 8, 325ra318.
  • Kagami, S., Rizzo, H.L., Lee, J.J., Koguchi, Y., and Blauvelt, A. (2010). Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J. Invest. Dermatol.. 130, 1373-1383.
  • Kai, K., Tanaka, T., Ide, T., Kawaguchi, A., Noshiro, H., and Aishima, S. (2021). Immunohistochemical analysis of the aggregation of CD1a-positive dendritic cells in resected specimens and its association with surgical outcomes for patients with gallbladder cancer. Transl. Oncol.. 14, 100923.
  • Kaplan, D.H., Igyarto, B.Z., and Gaspari, A.A. (2012). Early immune events in the induction of allergic contact dermatitis. Nat. Rev. Immunol.. 12, 114-124.
  • Kasmar, A.G., Van Rhijn, I., Magalhaes, K.G., Young, D.C., Cheng, T.Y., Turner, M.T., Schiefner, A., Kalathur, R.C., Wilson, I.A., and Bhati, M. (2013). Cutting Edge: CD1a tetramers and dextramers identify human lipopeptide-specific T cells ex vivo. J. Immunol.. 191, 4499-4503.
  • Kawano, T., Cui, J., Koezuka, Y., Toura, I., Kaneko, Y., Motoki, K., Ueno, H., Nakagawa, R., Sato, H., and Kondo, E. (1997). CD1d-restricted and TCR-mediated activation of vα14 NKT cells by glycosylceramides. Science. 278, 1626-1629.
  • Kim, J.H., Hu, Y., Yongqing, T., Kim, J., Hughes, V.A., Le Nours, J., Marquez, E.A., Purcell, A.W., Wan, Q., and Sugita, M. (2016). CD1a on Langerhans cells controls inflammatory skin disease. Nat. Immunol.. 17, 1159-1166.
  • Kinjo, Y., Tupin, E., Wu, D., Fujio, M., Garcia-Navarro, R., Benhnia, M.R., Zajonc, D.M., Ben-Menachem, G., Ainge, G.D., and Painter, G.F. (2006). Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat. Immunol.. 7, 978-986.
  • Kjer-Nielsen, L., Patel, O., Corbett, A.J., Le Nours, J., Meehan, B., Liu, L., Bhati, M., Chen, Z., Kostenko, L., and Reantragoon, R. (2012). MR1 presents microbial vitamin B metabolites to MAIT cells. Nature. 491, 717-723.
  • Lepore, M., de Lalla, C., Gundimeda, S.R., Gsellinger, H., Consonni, M., Garavaglia, C., Sansano, S., Piccolo, F., Scelfo, A., and Haussinger, D. (2014). A novel self-lipid antigen targets human T cells against CD1c+ leukemias. J. Exp. Med.. 211, 1363-1377.
  • Manolova, V., Kistowska, M., Paoletti, S., Baltariu, G.M., Bausinger, H., Hanau, D., Mori, L., and De Libero, G. (2006). Functional CD1a is stabilized by exogenous lipids. Eur. J. Immunol.. 36, 1083-1092.
  • Matsuda, J.L., Naidenko, O.V., Gapin, L., Nakayama, T., Taniguchi, M., Wang, C.R., Koezuka, Y., and Kronenberg, M. (2000). Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J. Exp. Med.. 192, 741-754.
  • Miller, C.J., McChesney, M., and Moore, P.F. (1992). Langerhans cells, macrophages and lymphocyte subsets in the cervix and vagina of rhesus macaques. Lab. Invest.. 67, 628-634.
  • Moody, D.B., Young, D.C., Cheng, T.Y., Rosat, J.P., Roura-Mir, C., O'Connor, P.B., Zajonc, D.M., Walz, A., Miller, M.J., and Levery, S.B. (2004). T cell activation by lipopeptide antigens. Science. 303, 527-531.
  • Nestle, F.O., Conrad, C., Tun-Kyi, A., Homey, B., Gombert, M., Boyman, O., Burg, G., Liu, Y.J., and Gilliet, M. (2005). Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J. Exp. Med.. 202, 135-143.
  • Nicolai, S., Wegrecki, M., Cheng, T.Y., Bourgeois, E.A., Cotton, R.N., Mayfield, J.A., Monnot, G.C., Le Nours, J., Van Rhijn, I., and Rossjohn, J. (2020). Human T cell response to CD1a and contact dermatitis allergens in botanical extracts and commercial skin care products. Sci. Immunol.. 5, eaax5430.
  • Park, S.H., Weiss, A., Benlagha, K., Kyin, T., Teyton, L., and Bendelac, A. (2001). The mouse CD1d-restricted repertoire is dominated by a few autoreactive T cell receptor families. J. Exp. Med.. 193, 893-904.
  • Porcelli, S., Brenner, M.B., Greenstein, J.L., Balk, S.P., Terhorst, C., and Bleicher, P.A. (1989). Recognition of cluster of differentiation 1 antigens by human CD4-CD8- cytolytic T lymphocytes. Nature. 341, 447-450.
  • Radwan, J., Babik, W., Kaufman, J., Lenz, T.L., and Winternitz, J. (2020). Advances in the evolutionary understanding of MHC polymorphism. Trends Genet.. 36, 298-311.
  • Raftery, M.J., Hitzler, M., Winau, F., Giese, T., Plachter, B., Kaufmann, S.H., and Schonrich, G. (2008). Inhibition of CD1 antigen presentation by human cytomegalovirus. J. Virol.. 82, 4308-4319.
  • Rosat, J.P., Grant, E.P., Beckman, E.M., Dascher, C.C., Sieling, P.A., Frederique, D., Modlin, R.L., Porcelli, S.A., Furlong, S.T., and Brenner, M.B. (1999). CD1-restricted microbial lipid antigen-specific recognition found in the CD8+ αβ T cell pool. J. Immunol.. 162, 366-371.
  • Salimi, M., Barlow, J.L., Saunders, S.P., Xue, L., Gutowska-Owsiak, D., Wang, X., Huang, L.C., Johnson, D., Scanlon, S.T., and McKenzie, A.N. (2013). A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J. Exp. Med.. 210, 2939-2950.
  • Sandel, M.H., Dadabayev, A.R., Menon, A.G., Morreau, H., Melief, C.J., Offringa, R., van der Burg, S.H., Janssen-van Rhijn, C.M., Ensink, N.G., and Tollenaar, R.A. (2005). Prognostic value of tumor-infiltrating dendritic cells in colorectal cancer: role of maturation status and intratumoral localization. Clin. Cancer Res.. 11, 2576-2582.
  • Scharf, L., Li, N.S., Hawk, A.J., Garzon, D., Zhang, T., Fox, L.M., Kazen, A.R., Shah, S., Haddadian, E.J., and Gumperz, J.E. (2010). The 2.5 Å structure of CD1c in complex with a mycobacterial lipid reveals an open groove ideally suited for diverse antigen presentation. Immunity. 33, 853-862.
  • Schnellhardt, S., Erber, R., Buttner-Herold, M., Rosahl, M.C., Ott, O.J., Strnad, V., Beckmann, M.W., King, L., Hartmann, A., and Fietkau, R. (2020). Tumour-infiltrating inflammatory cells in early breast cancer: an underrated prognostic and predictive factor?. Int. J. Mol. Sci.. 21, 8238.
  • Seshadri, C., Shenoy, M., Wells, R.D., Hensley-McBain, T., Andersen-Nissen, E., McElrath, M.J., Cheng, T.Y., Moody, D.B., and Hawn, T.R. (2013). Human CD1a deficiency is common and genetically regulated. J. Immunol.. 191, 1586-1593.
  • Shamshiev, A., Gober, H.J., Donda, A., Mazorra, Z., Mori, L., and De Libero, G. (2002). Presentation of the same glycolipid by different CD1 molecules. J. Exp. Med.. 195, 1013-1021.
  • Sharma, M., Zhang, X., Zhang, S., Niu, L., Ho, S.M., Chen, A., and Huang, S. (2017). Inhibition of endocytic lipid antigen presentation by common lipophilic environmental pollutants. Sci. Rep.. 7, 2085.
  • Sieling, P.A., Torrelles, J.B., Stenger, S., Chung, W., Burdick, A.E., Rea, T.H., Brennan, P.J., Belisle, J.T., Porcelli, S.A., and Modlin, R.L. (2005). The human CD1-restricted T cell repertoire is limited to cross-reactive antigens: implications for host responses against immunologically related pathogens. J. Immunol.. 174, 2637-2644.
  • Subramaniam, S., Aslam, A., Misbah, S.A., Salio, M., Cerundolo, V., Moody, D.B., and Ogg, G. (2016). Elevated and cross-responsive CD1a-reactive T cells in bee and wasp venom allergic individuals. Eur. J. Immunol.. 46, 242-252.
  • Sugita, M., Cao, X., Watts, G.F., Rogers, R.A., Bonifacino, J.S., and Brenner, M.B. (2002). Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity. 16, 697-706.
  • Sugita, M., Grant, E.P., van Donselaar, E., Hsu, V.W., Rogers, R.A., Peters, P.J., and Brenner, M.B. (1999). Separate pathways for antigen presentation by CD1 molecules. Immunity. 11, 743-752.
  • Sugita, M., Porcelli, S.A., and Brenner, M.B. (1997). Assembly and retention of CD1b heavy chains in the endoplasmic reticulum. J. Immunol.. 159, 2358-2365.
  • Sugita, M., van Der Wel, N., Rogers, R.A., Peters, P.J., and Brenner, M.B. (2000). CD1c molecules broadly survey the endocytic system. Proc. Natl. Acad. Sci. U. S. A.. 97, 8445-8450.
  • Suzuki, A., Masuda, A., Nagata, H., Kameoka, S., Kikawada, Y., Yamakawa, M., and Kasajima, T. (2002). Mature dendritic cells make clusters with T cells in the invasive margin of colorectal carcinoma. J. Pathol.. 196, 37-43.
  • Tazi, A., Bouchonnet, F., Grandsaigne, M., Boumsell, L., Hance, A.J., and Soler, P. (1993). Evidence that granulocyte macrophage-colony-stimulating factor regulates the distribution and differentiated state of dendritic cells/Langerhans cells in human lung and lung cancers. J. Clin. Invest.. 91, 566-576.
  • Vasquez, A.M., Mouchlis, V.D., and Dennis, E.A. (2018). Review of four major distinct types of human phospholipase A2. Adv. Biol. Regul.. 67, 212-218.
  • Visvabharathy, L., Genardi, S., Cao, L., He, Y., Alonzo, F., Berdyshev, E., and Wang, C.R. (2020). Group 1 CD1-restricted T cells contribute to control of systemic Staphylococcus aureus infection. PLoS Pathog.. 16, e1008443.
  • Vocanson, M., Hennino, A., Rozieres, A., Poyet, G., and Nicolas, J.F. (2009). Effector and regulatory mechanisms in allergic contact dermatitis. Allergy. 64, 1699-1714.
  • Wollenberg, A., Kraft, S., Hanau, D., and Bieber, T. (1996). Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J. Invest. Dermatol.. 106, 446-453.
  • Yoshida, A., Imayama, S., Sugai, S., Kawano, Y., and Ishibashi, T. (1997). Increased number of IgE positive Langerhans cells in the conjunctiva of patients with atopic dermatitis. Br. J. Ophthalmol.. 81, 402-406.
  • Zajonc, D.M., Crispin, M.D., Bowden, T.A., Young, D.C., Cheng, T.Y., Hu, J., Costello, C.E., Rudd, P.M., Dwek, R.A., and Miller, M.J. (2005). Molecular mechanism of lipopeptide presentation by CD1a. Immunity. 22, 209-219.
  • Zajonc, D.M., Elsliger, M.A., Teyton, L., and Wilson, I.A. (2003). Crystal structure of CD1a in complex with a sulfatide self antigen at a resolution of 2.15. Å. Nat. Immunol.. 4, 808-815.
  • Zeng, Z., Castano, A.R., Segelke, B.W., Stura, E.A., Peterson, P.A., and Wilson, I.A. (1997). Crystal structure of mouse CD1: an MHC-like fold with a large hydrophobic binding groove. Science. 277, 339-345.

Figure 1

(A) The structural feature of CD1a. The heavy chain consists of three domains (α1, α2, α3) with a short cytoplasmic tail, and it is non-covalently associated with a light chain (β2m). The α1 and α2 domains form the lipid antigen-binding groove, which bears two pockets, A′ and F′. (B) TCRs recognize CD1a-lipid complexes by three modes: head-group recognition (upper), absence of interference (middle) and interference (bottom). 1) Some TCRs interact with a specific head-group of lipids protruding out of the CD1a and form a ternary lipid-CD1a-TCR complex. 2) Some headless lipids are completely buried within antigen binding groove and allow TCRs the opportunity to directly bind to the A roof of CD1a. In this case, TCRs do not need interact with antigens, but CD1a itself. 3) Bulky head-groups of some lipids can interfere TCR:CD1a interaction, thereby controlling the activation of CD1a-autoreactive T cells. β2m, β2-microglobulin.

Figure 2

CD1a-expressing APCs are abundant, but not limited, in skin. Antigens of CD1a are derived from self or various foreign sources such as Mycobacteria, plants and cosmetics, and presented on CD1a in early/recycling endosomal compartments or at cell surface. Similar to the origins of antigens, host- or foreign-derived PLA2 can generate neoantigens of CD1a under certain conditions. CD1a-reactive T cells activated by recognizing the complex of CD1a and antigen or CD1a itself produce various cytokines, thereby controlling immune responses occurred in inflammatory skin diseases such as contact dermatitis, psoriasis and atopic dermatitis.