Laurent Gapin

Laurent Gapin
University of Colorado | UCD · Department of Immunology

Professor

About

128
Publications
10,324
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11,739
Citations
Citations since 2017
30 Research Items
3477 Citations
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20172018201920202021202220230100200300400500600
20172018201920202021202220230100200300400500600
Additional affiliations
November 2002 - present
November 2002 - present
University of Colorado
November 1998 - August 2002
La Jolla Institute for Allergy & Immunology

Publications

Publications (128)
Article
Innate T (Tinn) cells are a collection of T cells with important regulatory functions that have a crucial role in immunity towards tumors, bacteria, viruses, and in cell-mediated autoimmunity. In mice, the two main αβ Tinn cell subsets include the invariant NKT (iNKT) cells that recognize glycolipid antigens presented by non-polymorphic CD1d molecu...
Article
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CD1a-autoreactive T cells represent a significant proportion of circulating αβ T cells in humans and appear to be enriched in the skin. How their autoreactivity is regulated remains unclear. In this issue of JEM, Cotton et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202699) show that CD1a molecules do not randomly survey cellular lipids bu...
Article
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The CD4 ⁺ T cell response is critical to host protection against helminth infection. How this response varies across different hosts and tissues remains an important gap in our understanding. Using IL-4-reporter mice to identify responding CD4 ⁺ T cells to Nippostrongylus brasiliensis infection, T cell receptor sequencing paired with novel clusteri...
Article
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A recent boom in mucosal-associated invariant T (MAIT) cell research has identified relationships between MAIT cell abundance, function, and clinical outcomes in various malignancies. As they express a variety of immune checkpoint receptors and ligands, and possess strong cytotoxic functions, MAIT cells are an attractive new subject in the field of...
Article
Full-text available
Most T lymphocytes leave the thymus as naïve cells with limited functionality. However, unique populations of innate-like T cells differentiate into functionally distinct effector subsets during their development in the thymus. Here, we profiled >10,000 differentiating thymic invariant natural killer T (iNKT) cells using single-cell RNA sequencing...
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Methicillin-resistant Staphylococcus aureus (SA) bacteremia is responsible for over 10,000 deaths in the hospital setting each year. Both conventional CD4+ T cells and γδ T cells play protective roles in SA infection through secretion of IFN-γ and IL-17. However, the role of other unconventional T cells in SA infection is largely unknown. Natural k...
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Invariant Natural Killer T (iNKT) cells are particular T lymphocytes, at the frontier between innate and adaptative immunities. They participate in the elimination of pathogens or tumor cells, but also in the development of allergic reactions and autoimmune diseases. From their first descriptions, the phenomenon of self‐reactivity has been describe...
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Memory T cells respond rapidly in part because they are less reliant on heightened levels of costimulatory molecules. This enables rapid control of secondary infecting pathogens but presents challenges to efforts to control or silence memory CD4 T cells, for example in antigen specific tolerance strategies for autoimmunity. We have examined the tra...
Preprint
Full-text available
While much of the research concerning factors associated with responses to immunotherapies focuses on the contributions of conventional peptide-specific T cells, the role of unconventional T cells, such as mucosal-associated invariant T (MAIT) cells, in human melanoma remains largely unknown. MAIT cells are innate-like T cells expressing a semi-inv...
Preprint
Most T lymphocytes leave the thymus as naive cells with limited functionality. However, unique populations of T cells, commonly known as innate-like T cells, differentiate into functionally distinct effector subsets during thymic development under the influence of the transcription factor PLZF. Here, we profiled >10,000 differentiating thymic iNKT...
Preprint
Full-text available
Memory T cells respond rapidly in part because they are less reliant on heightened levels of costimulatory molecules. This presents challenges to silencing memory T cells in tolerance strategies for autoimmunity or allergy. We find that memory CD4 T cells generated by infection or immunisation survive secondary activation with antigen delivered wit...
Article
Full-text available
Significance Central to adaptive immunity is the interaction between the αβ T cell antigen receptor (TCR) and peptides presented by the major histocompatibility complex (MHC) molecules. It is fundamental to understand any potential generalities regarding a TCR-pMHC recognition event. Two theories have been proposed to explain how TCR recognition of...
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In type 1 diabetes (T1D), proinsulin is a major autoantigen and the insulin B:9-23 peptide contains epitopes for CD4 ⁺ T cells in both mice and humans. This peptide requires carboxyl-terminal mutations for uniform binding in the proper position within the mouse IA g7 or human DQ8 major histocompatibility complex (MHC) class II (MHCII) peptide groov...
Article
Immortalized T cells such as T cell hybridomas, transfectomas, and transductants are useful tools to study tri-molecular complexes consisting of peptide, MHC, and T cell receptor (TCR) molecules. These cells have been utilized for antigen discovery studies for decades due to simplicity and rapidness of growing cells. However, responsiveness to anti...
Article
Full-text available
During development in the thymus, invariant natural killer T (iNKT) cells commit to one of three major functionally different subsets, iNKT1, iNKT2, and iNKT17. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets, with strong signaling promoting iNKT2 and iNKT17 development. Altering TCR div...
Chapter
Natural killer T (NKT) cells are a subset of αβ T cells that recognize lipid antigens presented by the nonclassical MHC molecule CD1d. Although numerically small, these cells have been shown to play an important role in the regulation of multiple immune responses, including microbial infection, autoimmunity, and cancer. Even in the steady state, cy...
Article
Full-text available
Invariant natural killer T (iNKT) cells are a CD1d-restricted T cell population that can respond to lipid antigenic stimulation within minutes by secreting a wide variety of cytokines. This broad functional scope has placed iNKT cells at the frontlines of many kinds of immune responses. Although the diverse functional capacities of iNKT cells have...
Article
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MHC class I-like CD1 molecules have evolved to present lipid-based antigens to T cells. Differences in the antigen-binding clefts of the CD1 family members determine the conformation and size of the lipids that are presented, although the factors that shape CD1 diversity remain unclear. In mice, two homologous genes, CD1D1 and CD1D2, encode the CD1...
Data
In normal mice, a significant number of TCRα sequences appear on naïve CD4 T cells regardless of the selecting MHCII allele. Naïve CD4 T cells were isolated from the lymph nodes of normal mice of the indicated strains and their TCRα sequences identified as described in the Materials and methods section. Shown are the %s of unique sequences and the...
Data
Data from individual mice show that both CD4 and CD8 T cells appear in mice expressing a single TCRb chain regardless of the MHC allele expressed. The numbers of thymus and lymph node cells were counted and analyzed for their expression of CD4 and CD8 and T cell receptor.
Data
After transduction with the DObWT chain, T cells from mice expressing DOb48A react with cells bearing the MHC allele that selected them. CD4 T cells were isolated from individual DOb48A mice and transduced with retorviruses expressing DObWT or DOb48A as described in the Methods section. The cells were vultured with spoleen cells from mice expressin...
Article
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Mature T cells bearing αβ T cell receptors react with foreign antigens bound to alleles of major histocompatibility complex proteins (MHC) that they were exposed to during their development in the thymus, a phenomenon known as positive selection. The structural basis for positive selection has long been debated. Here, using mice expressing one of t...
Preprint
Full-text available
Mature T cells bearing αβ T cell receptors react with foreign antigens bound to alleles of major histocompatibility complex proteins (MHC) that they were exposed to during their development in the thymus, a phenomenon known as positive selection. The structural basis for positive selection has long been debated. Here, using mice expressing one of t...
Article
Mycobacterium tuberculosis synthesizes a thick cell wall comprised of mycolic acids (MA), which are foreign antigens for human T cells. T-cell clones from multiple donors were used to determine the fine-specificity of MA recognition by human αβ T cells. Most CD1-presented lipid antigens contain large hydrophilic head groups comprised of carbohydrat...
Article
The epigenetic regulation of gene expression by the histone demethylase UTX is central to the development of invariant natural killer cells.
Article
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CD1 proteins present microbial lipids to T cells. Germline-encoded mycolyl lipid-reactive (GEM) T cells with conserved αβ T cell receptors (TCRs) recognize CD1b presenting mycobacterial mycolates. As the molecular basis underpinning TCR recognition of CD1b remains unknown, here we determine the structure of a GEM TCR bound to CD1b presenting glucos...
Data
Supplementary Figures 1-7, Supplementary Tables 1-4, Supplementary References.
Article
Full-text available
Significance The evolutionary hypothesis for T-cell antigen receptor–peptide major histocompatibility complex (TCR–pMHC) interaction posits the existence of germ-line–encoded rules by which the TCR is biased toward recognition of the MHC. Understanding these rules is important for our knowledge of how to manipulate this important interaction at the...
Article
Full-text available
Polymorphic major histocompatibility complex (MHC) molecules play a central role in the vertebrate adaptive immune system. By presenting short peptides derived from pathogen-derived proteins, these “classical” MHC molecules can alert the T cell branch of the immune system of infected cells and clear the pathogen. There exist other “non-classical” M...
Article
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Invariant Natural Killer T (iNKT) cells are a unique subset of T lymphocytes that have been implicated in both promoting and suppressing a multitude of immune responses. In mice, iNKT cells express T cell antigen receptors (TCRs) comprising a unique TCRα rearrangement between the Trav11 and Traj18 gene segments. When paired with certain Trbv TCRβ c...
Article
Natural Killer T (NKT) cells are a class of αβ T cells that express a semi-invariant T Cell Receptor (TCR) and recognize glycolipids presented by the non-polymorphic MHC molecule, CD1d. NKT cells are considered to be innate-like lymphocytes because they produce a robust cytokine response within hours of stimulation. This ‘poised effector’ state is...
Article
Invariant natural killer T (iNKT) cells develop into functionally distinct subsets. Each subset expresses a unique combination of transcription factors that regulate cytokine gene transcription upon activation. The tissue distribution and localization within tissues also varies between subsets. Importantly, the relative abundance of the various sub...
Article
Full-text available
Adaptive immunity has long been considered the hallmark trait associated with jawed vertebrates. Although unconventional forms of adaptive immunity, such as variable lymphocyte receptors in lampreys (1) and CRISPR/Cas in bacteria (2), have recently gained recognition, somatic recombination generating unique antigen receptors provides diversity unpa...
Article
Conventional T cells have historically been linked to exacerbating allergy. By efficiently generating primarily TH 2 cells, allergens skew the immune response to produce IL-4, IL-13, and IgE. Previously, CD1a-responsive T cells were shown to functionally respond to bee and wasp venom allergens. In this issue of the European Journal of Immunology, S...
Article
Full-text available
Significance Traditional immunizations involve the controlled introduction of attenuated bacteria or viruses, allowing for generation of immunity prior to exposure to the dangerous native pathogen. In contrast, subunit immunization utilizes only pieces of the pathogen combined with a separate immune stimulatory agent (adjuvant). Although subunit im...
Article
The evolutionary conservation of T lymphocyte subsets bearing αβ TCRs using invariant α-chains is indicative of unique and important functions. Among these T lymphocytes, NKT cells that express an invariant TCRα-chain and recognize lipid Ags presented by the nonclassical MHC class I molecule CD1d are probably the most studied. However, a new popula...
Article
Full-text available
Significance Several different populations of T lymphocytes develop in the thymus from a common precursor. Each population plays a unique and critical role in the mounting and resolution of an immune response. The mechanisms responsible for the emergence of these different populations remain incompletely understood. We demonstrate that strict “Gold...
Article
Mucosal-associated invariant T cells are a unique population of T cells that express a semi-invariant αβ TCR and are restricted by the MHC class I-related molecule MR1. MAIT cells recognize uncharacterized ligand(s) presented by MR1 through the cognate interaction between their TCR and MR1. To understand how the MAIT TCR recognizes MR1 at the surfa...
Article
NKT cell function in animal models is highly variable. This variation is likely due to functionally distinct subpopulations of NKT cells that are present to different degrees in each mouse strain. NKT precursors proceed through several developmental stages marked by the sequential expression of activation markers and NK cell receptors. At each step...
Article
Various populations of memory phenotype CD8+ T cells have been described over the last 15-20 years, all of which possess elevated effector functions relative to naïve phenotype cells. Using a technique for isolating antigen specific cells from unprimed hosts, we recently identified a new subset of cells, specific for nominal antigen, but phenotypic...
Article
Natural Killer T (NKT) cells are distinct lymphocyte lineages that recognize lipid antigens presented by the non-classical Major Histocompatibility Complex molecule CD1d. Two categories of NKT cells, type I and type II, have been described based on T-cell receptor expression and antigenic specificity. In both cases, increasing evidence suggest that...
Article
Full-text available
Various populations of memory phenotype CD8(+) T cells have been described over the last 15-20 y, all of which possess elevated effector functions relative to naive phenotype cells. Using a technique for isolating Ag-specific cells from unprimed hosts, we recently identified a new subset of cells, specific for nominal Ag, but phenotypically and fun...
Article
Full-text available
Mucosal-associated invariant T cells are a unique population of T cells that express a semi-invariant αβ TCR and are restricted by the MHC class I-related molecule MR1. MAIT cells recognize uncharacterized ligand(s) presented by MR1 through the cognate interaction between their TCR and MR1. To understand how the MAIT TCR recognizes MR1 at the surfa...
Data
Comparison of orthologous Vα19-Jα33 gene segments in several species that express MR1. (A) Rooted phylogenic tree of TRAV1, TRAV11 and TRAV19 orthologues from 16 different mammalian species. (B) Sequence alignment of TRAV1 and TRAJ33 orthologues from 16 different mammalian species. Conserved cysteine residues important to the immunoglobulin fold ar...
Data
Response of 6C2 MAIT hybridoma to fibroblasts overexpressing mouse MR1 (hatched bars) or untransduced fibroblasts (gray bars) cocultured with E. coli at indicated MOI. MR1 blocking antibody 26.5 (20 µg/mL) was used to inhibit the response of the hybridoma to wild-type fibroblasts (black bars) co-cultured with E. coli. ELISA of IL-2 production by hy...
Article
T lymphocytes express clonal receptors, called T cell receptors (TCRs), which specifically recognize antigens presented in combination with major histocompatibility molecules (MHC). To date, T cell antigens can be broadly categorized into two classes: peptides and lipids. A recent paper published in Nature by Kjer-Nielsen and colleagues reveals tha...
Article
Full-text available
Natural killer T (NKT) cells are innate-like T cells that rapidly produce a variety of cytokines following T cell receptor (TCR) activation and can shape the immune response in many different settings. There are two main NKT cell subsets: type I NKT cells are typically characterized by the expression of a semi-invariant TCR, whereas the TCRs expres...
Article
T cells bearing receptors made up of α and β chains (TCRs) usually react with peptides bound to major histocompatibility complex proteins (MHC). This bias could be imposed by positive selection, the phenomenon that selects thymocytes to mature into T cells only if the TCRs they bear react with low but appreciable affinity with MHC + peptide combina...
Article
Full-text available
The T cell response to B cell lymphomas differs from the majority of solid tumors in that the malignant cells themselves are derived from B lymphocytes, key players in immune response. B cell lymphomas are therefore well situated to manipulate their surrounding microenvironment to enhance tumor growth and minimize anti-tumor T cell responses. We an...
Data
Reconstitution of iNKT cells in Jalpha18−/− mice restores tumor growth. Lethally irradiated Jalpha18−/− mice were reconstituted with either WT or control Jalpha18−/− bone marrow. After ∼8 weeks, we inoculated mice with 105 TBL-GFP cells intravenously. (A) The number of tumor cells among LN, spleen, and IHL was determined 14 days after transplant by...
Data
Tumor growth for TBL lymphoma cells. WT mice were transplanted with 105 lymphoma cells i.v. Tumor growth was assessed in the LN, spleen, and liver (intrahepatic leukocytes, IHL) on days 6, 8, 10, 12, and 14 post-transplant. Data are (A) representative FACS plots or (B) quantitation of 3 independent experiments. (TIF)
Article
Full-text available
Natural killer T cells (NKT cells) are divided into type I and type II subsets on the basis of differences in their T cell antigen receptor (TCR) repertoire and CD1d-antigen specificity. Although the mode by which type I NKT cell TCRs recognize CD1d-antigen has been established, how type II NKT cell TCRs engage CD1d-antigen is unknown. Here we prov...
Article
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There is accumulating evidence that autoimmunity to insulin B chain peptide, amino acids 9-23 (insulin B:9-23), is central to development of autoimmune diabetes of the NOD mouse model. We hypothesized that enhanced susceptibility to autoimmune diabetes is the result of targeting of insulin by a T-cell receptor (TCR) sequence commonly encoded in the...
Article
We have investigated the role of CD40 signaling in islet-reactive, diabetogenic CD4(+) Th1 T-cell clones. Using multispectral flow cytometry, we showed that CD40 and CD154 are co-expressed and form complexes on the surface of activated T cells. We also demonstrate that activated Tcells can transactivate CD4(+) CD40(+) T cells through the CD40-CD154...
Article
Full-text available
Natural killer T cell antigen receptors (NKT TCRs) recognize lipid-based antigens (Ags) presented by CD1d. Although the TCR α-chain is invariant, NKT TCR Vβ exhibits greater diversity, with one (Vβ11) and three (Vβ8, Vβ7, and Vβ2) Vβ chains in humans and mice, respectively. With the exception of the Vβ2 NKT TCR, NKT TCRs possess canonical tyrosine...
Article
Full-text available
αβ T cell receptors (TCRs) bind specifically to foreign antigens presented by major histocompatibility complex proteins (MHC) or MHC-like molecules. Accumulating evidence indicates that the germline-encoded TCR segments have features that promote binding to MHC and MHC-like molecules, suggesting coevolution between TCR and MHC molecules. Here, we a...
Article
Full-text available
The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids, whereas NKT cell self-reactivity involves weaker recognition of structurally distinct β-linked glycolipid antigens. Here we provide the mechanism for the autoreactivity of T cell antigen receptors (TCRs) on NKT cells to the mono- and tri-glycosylated β...
Article
Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells mediated by self-reactive CD4 T cells. Our objective in this study was to determine how CD40 on autoreactive CD4 T cells contributes to their pathogenicity. BDC-5.2.9 is a highly diabetogenic CD4 T cell clone and expresses the costimulatory molecule CD40 which can inte...
Article
Natural killer T (NKT) cells respond to a variety of CD1d-restricted antigens (Ags), although the basis for Ag discrimination by the NKT cell receptor (TCR) is unclear. Here we have described NKT TCR fine specificity against several closely related Ags, termed altered glycolipid ligands (AGLs), which differentially stimulate NKT cells. The structur...
Article
The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and self-lipid antigens, although the molecular basis of self-CD1d recognition is unclear. Here, we have characterized NKT TCR recognition of CD1d molecules loaded with natural self-antigens (Ags) and report the 2.3 Å resolution structure of an autoreactive NK...
Article
The recognition of lipid antigens by T cells is a complex and fascinating phenomenon. The MHC-like molecules of the CD1 family have evolved to present a wide variety of both self and foreign lipids for recognition by T-cell receptors. While much progress has been made in our understanding of the Natural Killer T (NKT) cells that recognize lipids pr...
Article
Full-text available
The αβreceptors on T cells (TCRs) nearly always recognize peptides from antigens bound to host major histocompatibility complex proteins (MHC). We and others have found some of the residues on TCRs that control their ability to react with MHC. The same TCR residues are used to bind both MHCI and MHCII. This property of TCRs have been inherited thro...
Article
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Invariant NKT cells (iNKT cells) play a pivotal role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation. However, it is unclear what role they play in the initiation (sensitization) phase as opposed to the effector (challenge) phase. The role of iNKT cells during sensitization was examined by determining the re...
Article
Following stimulation through their T cell receptor, invariant natural killer T (iNKT) cells function as innate effector cells by rapidly releasing large amounts of effector cytokines and chemokines and therefore have an important role in modulating the ensuing immune response. iNKT cells recognize, and are activated by, diverse glycolipid antigens...
Article
Full-text available
The semi-invariant natural killer (NK) T-cell receptor (NKTcr) recognises structurally diverse glycolipid antigens presented by the monomorphic CD1d molecule. While the alpha-chain of the NKTcr is invariant, the beta-chain is more diverse, but how this diversity enables the NKTcr to recognise diverse antigens, such as an alpha-linked monosaccharide...
Article
We have previously shown that Toll-like receptor (TLR) agonists cooperate with CD40 to generate CD8 T cell responses exponentially larger than the responses generated with traditional vaccine formulations. We have also shown that combined TLR agonist/anti-CD40 immunization uniquely induces the upregulation of CD70 on antigen bearing dendritic cells...