Human CD1a Deficiency Is Common and Genetically Regulated

Seshadri, Chetan; Shenoy, Meera K.; Wells, Richard D.; Hensley-McBain, Tiffany; Andersen‐Nissen, Erica; McElrath, M. Juliana; Cheng, Tan Yun; Moody, D. Branch; Hawn, Thomas R.

doi:10.4049/jimmunol.1300575

Cited by 38 publications

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References 42 publications

(49 reference statements)

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“…These inflammatory DCs are reported as crucial antigen presenting cells able to initiate a pathogen-specific immune response and to play a critical role in the control of inflammation and infection [36,37]. Individuals with mutations in the promotor region of CD1A show a total lack of CD1a expression [13], but individuals for whom the level of CD1a on DCs is low or moderate, but not null, also exist. Among these individuals a diverse and donorspecific capacity for CD1a induction on DCs is now established through the decreased production of IL12p70 and CCL1 associated with CD1a low expression [11].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The expression of CD1a on iDCs obtained from monocytes varies among individuals [10,11]. Furthermore, certain individuals have a total lack of CD1a due to a mutation in the 5'UTR region of CD1A [13].Transcriptional regulation of the expression of CD1a is complex and has only been partially deciphered. Regulation depends on components of the extracellular environment such as lipids that activate the PPAR-γ receptor [11] or immunoglobulins acting via their binding to FcγRIIa [14].…”

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confidence: 99%

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CD99 isoforms regulate CD1a expression in human monocyte‐derived DCs through ATF‐2/CREB‐1 phosphorylation

et al. 2016

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CD1a expression is considered one of the major characteristics qualifying in vitro human dendritic cells (DCs) during their generation process. Here, we report that CD1A transcription is regulated by a mechanism involving the long and short isoforms of CD99. Using a lentiviral construct encoding for a CD99 short hairpin RNA, we were able to inhibit CD99 expression in human primary DCs. In such cells, CD1a membrane expression increased and CD1A transcripts were much higher in abundance compared to cells expressing CD99 long form (CD99LF). We also show that CD1A transcription is accompanied by a switch in expression from CD99LF to expression at comparable levels of both CD99 isoforms during immature DCs generation in vitro. We demonstrate that CD99LF maintains a lower level of CD1A transcription by up-regulating the phosphorylated form of the ATF-2 transcription factor and that CD99 short form (SF) is required to counteract this regulatory mechanism. Elucidation of the molecular mechanisms related to CD99 alternative splicing will be very helpful to better understand the transcriptional regulatory mechanism of CD1a molecules during DCs differentiation and its involvement in the immune response.Keywords: alternative splicing-ATF2-CREB1 r CD99 r Dendritic cells r Nonclassical MHC Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPresentation of foreign antigens in the form of proteins or lipids solicits specialized molecular complexes carried by dendritic cells (DCs). The molecules of the classical and nonclassical major Correspondence: Dr. Ghislaine Bernard e-mail: bernardg@unice.fr histocompatibility complex (MHC) class I present antigens to T cells and these two families of molecules have very similar structures [1][2][3].Among the nonclassical MHC molecules is the CD1 family of molecules that assures the presentation of lipid and glycolipid † Deceased C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1460-1471 Immunomodulation 1461 antigens [4,5]. This family consists of five genes, including CD1A, B, C, D and E. The first four give rise to cell surface proteins CD1a, CD1b, CD1c, CD1d that are able to present the antigens, while the gene CD1E codes for the cytoplasmic protein CD1e [6][7][8]. CD1a is expressed on the membranes of thymocytes, dermal DCs and Langerhans cells, and allows distinction between subpopulations of DCs. No such equivalent has been reported in mice [8].CD1a is expressed during generation of DCs derived from monocytes when cultured in the presence of GMCSF and IL4 in vitro [9]. Two subpopulations of immature DCs (iDCs), i.e. CD1a high and CD1a low DCs, are produced in these conditions [10,11]. In addition to their phenotypic differences, these cells show functional differences, in particular in terms of secretion of cytokines. In contrast to CD1a high DCs, CD1a low DCs produce low amounts of IL12 but produce high amounts of IL10. This profile of cytokines impacts on the f...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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CD99 isoforms regulate CD1a expression in human monocyte‐derived DCs through ATF‐2/CREB‐1 phosphorylation

et al. 2016

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“…Single nucleotide polymorphisms in CD1a and CD1d have been described, but the affected amino acids are not located in or near the antigen binding groove or the TCR binding surface (3), which justifies the common description of CD1 genes as non-polymorphic. Unlike Doherty and Zinkernagel's experiments, CD1-reactive T cells from Donor A will respond to antigen presented by APCs from any human, with the only known exception that CD1a expression levels differ among donors (4). …”

Section: Unrestricted T Cellsmentioning

confidence: 94%

Donor Unrestricted T Cells: A Shared Human T Cell Response

Rhijn

Moody

2015

The Journal of Immunology

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The now famous term ‘restriction’ derived from experiments in which T cells from donor A failed to recognize antigens presented by cells from donor B. Restriction results from interdonor variation in major histocompatibility complex (MHC) genes. Donor restriction dominates immunologists' thinking about T cell response because it governs organ transplantation and hinders discovery of disease-associated antigens. However, other T cells can be considered ‘donor unrestricted’ because their targets, CD1a, CD1b, CD1c, CD1d or MR1, are expressed in a similar form among all humans. A striking feature of donor unrestricted T cells is the expression of invariant T cell receptors (TCRs) with nearly species-wide distribution. Here we review new evidence that donor unrestricted T cells are common in humans. NKT cells, MAIT cells and germline-encoded mycolyl-reactive (GEM) T cells operate outside the familiar principles of the MHC system, providing a broader picture of T cell function and new opportunities for therapy.

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“…Indeed, a unique SNP in the 5 0 untranslated region of the human CD1a gene is associated with altered expression of CD1a and antigen presentation (Seshadri et al 2013).…”

Section: Structure Expression and Intracellular Trafficking Of Cd1 mentioning

confidence: 99%

Nonclassical T Cells and Their Antigens in Tuberculosis

Libero

Singhal

Lepore

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Correspondence: gennaro_delibero@immunol.a-star.edu.sg T cells that recognize nonpeptidic antigens, and thereby are identified as nonclassical, represent important yet poorly characterized effectors of the immune response. They are present in large numbers in circulating blood and tissues and are as abundant as T cells recognizing peptide antigens. Nonclassical T cells exert multiple functions including immunoregulation, tumor control, and protection against infections. They recognize complexes of nonpeptidic antigens such as lipid and glycolipid molecules, vitamin B 2 precursors, and phosphorylated metabolites of the mevalonate pathway. Each of these antigens is presented by antigen-presenting molecules other than major histocompatibility complex (MHC), including CD1, MHC class I-related molecule 1 (MR1), and butyrophilin 3A1 (BTN3A1) molecules. Here, we discuss how nonclassical T cells participate in the recognition of mycobacterial antigens and in the mycobacterial-specific immune response.T he recognition by T lymphocytes of antigenic complexes formed by antigens and antigen-presenting molecules is a hallmark of the adaptive immune system. Awide range of exogenous and endogenous antigenic molecules reflecting a variety of chemical structures have been identified and are represented by proteins, lipids, phosphorylated metabolites, or vitamin B 2 pathway metabolites. The role of classical T cells, which recognize peptidic antigens associated with MHC-encoded molecules, during Mycobacterium tuberculosis (MTB) infection is well documented and studied for a long time (Cooper 2009). On the contrary, nonclassical T cells recognizing nonpeptidic antigens associated with non-MHC antigen-presenting molecules have been described more recently. They have also been identified as important contributors to host defense against infections, although many aspects of their physiological role still remain to be discovered. Based on the restriction molecule, antigen specificity, and T-cell receptor (TCR) structure, non-MHC-restricted T cells can be grouped into three categories: lipid-and glycolipid-specific CD1-restricted T cells, mucosal-associated invariant T (MAIT) MR1-restricted cells, and TCR gd BTN3A1-restricted T cells. In this article, we review critical issues of the basic immunobiology of non-MHC-restricted T cells related to recognition of Editors:

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Human CD1a Deficiency Is Common and Genetically Regulated

Cited by 38 publications

References 42 publications

CD99 isoforms regulate CD1a expression in human monocyte‐derived DCs through ATF‐2/CREB‐1 phosphorylation

CD99 isoforms regulate CD1a expression in human monocyte‐derived DCs through ATF‐2/CREB‐1 phosphorylation

Donor Unrestricted T Cells: A Shared Human T Cell Response

Nonclassical T Cells and Their Antigens in Tuberculosis

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