Group 1 CD1-restricted T cells

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Group 1 CD1-restricted T cells are a heterogeneous group of unconventional T cells defined by their ability to recognize antigens bound on group 1 CD1 molecules (CD1a, CD1b and CD1c) with their TCR. Natural killer T (NKT) cells are a similar population with affinity to CD1d (the only group 2 CD1 molecule). Both groups recognize lipid antigens in contrast to the conventional peptide antigens presented on MHC class 1 and 2 proteins. Most identified T-cells that bind group 1 CD1 proteins are αβ T cells and some are γδ T cells. Both foreign and endogenous lipid antigens activate these cells. [1] [2]

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The TCR usually recognizes the hydrophilic part of the antigen which protrudes outwards from the CD1 protein after the lipid chains are bound in a groove. Small hydrophobic antigens lacking a polar part have also been shown to activate CD1a-restricted T cells, indicating that in this case the TCR may bind CD1 directly following displacement of nonimmunogenic ligands. [3]

Group 1 CD1 proteins

Group 1 CD1 (CD1a, CD1b, CD1c) is a family of surface glycoproteins expressed on Dendritic cells, Langerhans cells and in some stages of thymocyte maturation. Some subsets of B cells express CD1c. These proteins are related to MHC class 1 molecules but have a high affinity for the lipidic moieties of antigens. Mice lack any counterpart for group 1 CD1 proteins, which has complicated the research of in vivo function. [4]

CD1 proteins are structurally similar to MHC class 1 proteins, containing 3 domains and non-covalently bound β2 microglobulin. They lack the genetic diversity typical of MHC genes and have a very limited number of polymorphisms, most of which produce silent mutations. Their variability reflects the limited scale of the lipid repertoire found in organisms compared to the large variety of proteins. Proteins can also easily acquire mutations, whereas the multi-step process of lipid synthesis is much less likely to change. [4]

On their way through the endoplasmic reticulum and Golgi apparatus they acquire nonimmunogenic lipid spacers. These spacers were identified to be diacylglycerides or deoxyceramides and their variety may explain the broad range of lipid chain lengths that group 1 CD1 proteins can accommodate, as the spacers have been observed to slide into different positions for different antigens. [5] After CD1 proteins reach the surface of the cell, they are internalized and the members show different patterns of localization with CD1b trafficking through late endosomes and lysosomes and CD1a localizing mostly in early endosomes. CD1c broadly localizes in a combination of the above mentioned compartments. CD1 proteins exchange their spacers for immunogenic ligands in endosomes and lysosomes with the help of several lipid transfer proteins (including CD1e). [4]

Function

In vivo studies have been hindered by the lack of orthologous proteins in mice. Humanized or transgenic mice are used to overcome this discrepancy and some studies use different animal species. Their function in Mycobacterium tuberculosis infection has been the main focus in past research. [2]

Group 1 CD1-restricted T cells are more similar to conventional T cells because their response takes days to weeks and they exhibit an accelerated response after prior immunization. This differs from their group 2 counterparts (Natural killer T ceCortical thymocyteslls) which react swiftly but undergo anergy following reexposure. [6]

Mycobacterium tuberculosis infection

Many lipid antigens of Mycobacterium tuberculosis have been identified, including: mycolic acid, glucose and glycerol monomycolates, lipoarabinomannan, phosphatidylinositol mannoside, diacylsulfoglycolipid, mannosyl-β-1-phosphomycoketide and didehydroxymycobactin. Most of these antigens are bound to CD1b. [5]

Group 1 CD1-restricted T cells are activated after Mycobacterium infection and produce IFN-γ and TNF-α (Th1 type response). These cells can be double negative (CD4−CD8−), CD4+ or CD8+ and possess strong cytotoxic capabilities. Studies using CD1b tetramers presenting the mycobacterial product glucose monomycolate identified two CD4+ TCRαβ+ T cell populations which differ from the otherwise variable TCR composition of previously isolated subsets, one termed 'GEM (Germline-encoded, mycolyl-reactive)' for their conserved TCR repertoire (specifically TRAV1-2+TRAJ9+) and 'LDN5-like' (TRBV4-1+). These cells are rare in individuals that have not encountered Mycobacterium tuberculosis. [1]

CD1 expression is downregulated in antigen presenting cells infected with live Mycobacteria, perhaps as a means of immune evasion. This downregulation can be also found in some leukemia cells. [4]

Autoreactivity

Group 1 CD1-restricted T cells can be activated by endogenous lipids, including gangliosides (GM1,GD1a, GD1b, GT1b, and GQ1b), sulfatides, sphingomyelin, phophatidylglycerol, lysophospholipids, squalene, wax esters, and triacylglycerides. [5]

Methyl-lysophosphatidic acids (mLPAs) are rare in healthy monocytes and B cells but are abundant in leukemic cells. CD1c self-reactive T cells were found to kill acute leukemia cells expressing CD1c binding these lipids. [7]

CD1a self-reactive T cells were found in the blood of healthy individuals. [8] These cells express skin-homing receptors and produce interleukin 22 after binding CD1a on Langerhans cells. CD1a binds many endogenous lipids found in skin-oil and is able to activate T-cells even with ligands that lack a hydrophilic part, e.g. squalene. [2] [3]

CD8+ TCR αβ+ CD1b T cells have been found in the central nervous system of patients with multiple sclerosis. They recognized glycolipids and secreted IFN-γ and TNF-α. [9]

Other autoimmune diseases where group 1 CD1 restricted T cells might contribute include psoriasis and systemic lupus erythematosus. [10]

Related Research Articles

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.

<span class="mw-page-title-main">CD4</span> Marker on immune cells

In molecular biology, CD4 is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984. In humans, the CD4 protein is encoded by the CD4 gene.

<span class="mw-page-title-main">T-cell receptor</span> Protein complex on the surface of T cells that recognises antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

CD1 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 to T cells. Both αβ and γδ T cells recognise CD1 molecules.

A thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood.

<span class="mw-page-title-main">CD1D</span> Mammalian protein found in Homo sapiens

CD1D is the human gene that encodes the protein CD1d, a member of the CD1 family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are non-classical MHC proteins, related to the class I MHC proteins, and are involved in the presentation of lipid antigens to T cells. CD1d is the only member of the group 2 CD1 molecules.

<span class="mw-page-title-main">Antigen presentation</span> Vital immune process that is essential for T cell immune response triggering

Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment can be recognized by a T-cell receptor. Specifically, the fragment, bound to the major histocompatibility complex (MHC), is transported to the surface of the cell, a process known as presentation. If there has been an infection with viruses or bacteria, the cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.

Understanding of the antitumor immunity role of CD4+ T cells has grown substantially since the late 1990s. CD4+ T cells (mature T-helper cells) play an important role in modulating immune responses to pathogens and tumor cells, and are important in orchestrating overall immune responses.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

<span class="mw-page-title-main">Lymphocyte-activation gene 3</span>

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

<span class="mw-page-title-main">CD1A</span> Mammalian protein found in Homo sapiens

CD1a is a human protein encoded by the CD1A gene.

MHC multimers are oligomeric forms of MHC molecules, designed to identify and isolate T-cells with high affinity to specific antigens amid a large group of unrelated T-cells. Multimers generally range in size from dimers to octamers; however, some companies use even higher quantities of MHC per multimer. Multimers may be used to display class 1 MHC, class 2 MHC, or nonclassical molecules from species such as monkeys, mice, and humans.

Natural killer T (NKT) cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. Many of these cells recognize the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self and foreign lipids and glycolipids. They constitute only approximately 1% of all peripheral blood T cells. Natural killer T cells should neither be confused with natural killer cells nor killer T cells.

T-cell receptor revision is a process in the peripheral immune system which is used by mature T cells to alter their original antigenic specificity based on rearranged T cell receptors (TCR). This process can lead either to continuous appearance of potentially self-reactive T cells in the body, not controlled by the central tolerance mechanism in the thymus or better eliminate such self-reactive T cells on the other hand and thus contributing to peripheral tolerance - the extent of each has not been completely understood yet. This process occurs during follicular helper T cell formation in lymph node germinal centers.

<span class="mw-page-title-main">CD1b</span> Mammalian protein found in Homo sapiens

T-cell surface glycoprotein CD1b is a protein that in humans is encoded by the CD1B gene.

Cd1-restricted T cells are part of the unconventional T cell family, they are stimulated by exposure to CD1+ antigen presenting cells (APCs). Many CD1-restricted T cells are rapidly stimulated to carry out helper and effector functions upon interaction with CD1-expressing antigen-presenting cells. CD1-restricted T cells regulate host defence, antitumor immunity and the balance between tolerance and autoimmunity.

References

  1. 1 2 Kabelitz D (2017-05-24). "Faculty Opinions Recommendation of [Godfrey DI et al., Nat Immunol 2015 16(11):1114-1123". Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. doi: 10.3410/f.725857548.793532503 .
  2. 1 2 3 Siddiqui S, Visvabharathy L, Wang CR (2015). "Role of Group 1 CD1-Restricted T Cells in Infectious Disease". Frontiers in Immunology. 6: 337. doi: 10.3389/fimmu.2015.00337 . PMC   4484338 . PMID   26175733.
  3. 1 2 de Jong A, Cheng TY, Huang S, Gras S, Birkinshaw RW, Kasmar AG, et al. (February 2014). "CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens". Nature Immunology. 15 (2): 177–185. doi:10.1038/ni.2790. PMC   3932764 . PMID   24362891.
  4. 1 2 3 4 Brigl M, Brenner MB (2004-04-01). "CD1: antigen presentation and T cell function". Annual Review of Immunology. 22 (1): 817–890. doi:10.1146/annurev.immunol.22.012703.104608. PMID   15032598.
  5. 1 2 3 Mori L, Lepore M, De Libero G (May 2016). "The Immunology of CD1- and MR1-Restricted T Cells". Annual Review of Immunology. 34 (1): 479–510. doi:10.1146/annurev-immunol-032414-112008. PMID   26927205.
  6. ↑ Felio K, Nguyen H, Dascher CC, Choi HJ, Li S, Zimmer MI, et al. (October 2009). "CD1-restricted adaptive immune responses to Mycobacteria in human group 1 CD1 transgenic mice". The Journal of Experimental Medicine. 206 (11): 2497–2509. doi:10.1084/jem.20090898. PMC   2768849 . PMID   19808251.
  7. ↑ Lepore M, de Lalla C, Gundimeda SR, Gsellinger H, Consonni M, Garavaglia C, et al. (June 2014). "A novel self-lipid antigen targets human T cells against CD1c(+) leukemias". The Journal of Experimental Medicine. 211 (7): 1363–1377. doi:10.1084/jem.20140410. PMC   4076585 . PMID   24935257. S2CID   337069.
  8. ↑ de Jong A, Peña-Cruz V, Cheng TY, Clark RA, Van Rhijn I, Moody DB (December 2010). "CD1a-autoreactive T cells are a normal component of the human αβ T cell repertoire". Nature Immunology. 11 (12): 1102–1109. doi:10.1038/ni.1956. PMC   3131223 . PMID   21037579.
  9. ↑ Shamshiev A, Donda A, Carena I, Mori L, Kappos L, De Libero G (May 1999). "Self glycolipids as T-cell autoantigens". European Journal of Immunology. 29 (5): 1667–1675. doi:10.1002/(sici)1521-4141(199905)29:05<1667::aid-immu1667>3.0.co;2-u. PMID   10359121. S2CID   13770737.
  10. ↑ Bagchi S, Genardi S, Wang CR (2018-07-16). "Linking CD1-Restricted T Cells With Autoimmunity and Dyslipidemia: Lipid Levels Matter". Frontiers in Immunology. 9: 1616. doi: 10.3389/fimmu.2018.01616 . PMC   6055000 . PMID   30061888.
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