Restricting nonclassical MHC genes coevolve with TRAV genes used by innate-like T cells in mammals

Whereas major histocompatibility class-1 (MH1) proteins present peptides to T cells displaying a large T-cell receptor (TR) repertoire, MH1Like proteins, such as CD1D and MR1, present glycolipids and microbial riboflavin precursor derivatives, respectively, to T cells expressing invariant TR-α (iTRA) chains. The groove of such MH1Like, as well as iTRA chains used by mucosal-associated invariant T (MAIT) and natural killer T (NKT) cells, respectively, may result from a coevolution under particular selection pressures. Herein, we investigated the evolutionary patterns of the iTRA of MAIT and NKT cells and restricting MH1Like proteins: MR1 appeared 170 Mya and is highly conserved across mammals, evolving more slowly than other MH1Like. It has been pseudogenized or independently lost three times in carnivores, the armadillo, and lagomorphs. The corresponding TRAV1 gene also evolved slowly and harbors highly conserved complementarity determining regions 1 and 2. TRAV1 is absent exclusively from species in which MR1 is lacking, suggesting that its loss released the purifying selection on MR1. In the rabbit, which has very few NKT and no MAIT cells, a previously unrecognized iTRA was identified by sequencing leukocyte RNA. This iTRA uses TRAV41, which is highly conserved across several groups of mammals. A rabbit MH1Like gene was found that appeared with mammals and is highly conserved. It was independently lost in a few groups in which MR1 is present, like primates and Muridae, illustrating compensatory emergences of new MH1Like/Invariant T-cell combinations during evolution. Deciphering their role is warranted to search similar effector functions in humans.

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Enhancing and inhibitory motifs have coevolved to regulate CD4 activity

10.1101/2021.04.29.441928 ◽

2021 ◽

Author(s):

Mark S. Lee ◽

Peter J. Tuohy ◽

Caleb Kim ◽

Katrina Lichauco ◽

Heather L. Parrish ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Purifying Selection ◽

Cell Receptor ◽

Specific Information ◽

Transmembrane Receptors ◽

Peptide Antigens ◽

And Function ◽

Intracellular Domains

SUMMARYCD4+ T cells use T cell receptor (TCR)-CD3 complexes, and CD4, to respond to peptide antigens within MHCII molecules (pMHCII). We report here that, through ∼435 million years of evolution in jawed vertebrates, purifying selection has shaped motifs in the extracellular, transmembrane, and intracellular domains of eutherian CD4 that both enhance pMHCII responses and are coevolving with residues in an intracellular motif that inhibits pMHCII responses. Importantly, while CD4 interactions with the Src kinase, Lck, are classically viewed as the key determinant of CD4’s contribution to pMHCII responses, we found that without the inhibitory motif CD4-Lck interactions are not necessary for robust responses to pMHCII. In summary, motifs that mediate events on the outside and inside of CD4+ T cells coevolved to finetune the relay of pMHCII-specific information across the membrane. These results have implications for the evolution and function of complex transmembrane receptors and for biomimetic engineering.

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Natural killer T cells in lipoprotein metabolism and atherosclerosis

Thrombosis and Haemostasis ◽

10.1160/th11-05-0336 ◽

2011 ◽

Vol 106 (11) ◽

pp. 814-819 ◽

Cited By ~ 28

Author(s):

Godfrey Getz ◽

Paul VanderLaan ◽

Catherine Reardon

Keyword(s):

T Cells ◽

T Cell ◽

Natural Killer ◽

Cell Receptor ◽

Nkt Cells ◽

Inflammatory Disorder ◽

Chronic Inflammatory Disorder ◽

Invariant Nkt Cells ◽

Adaptive Immune ◽

Natural Killer T

SummaryCells of both the innate and adaptive immune system participate in the development of atherosclerosis, a chronic inflammatory disorder of medium and large arteries. Natural killer T (NKT) cells express surface markers characteristic of natural killer cells and conventional T cells and bridge the innate and adaptive immune systems. The development and activation of NKT cells is dependent upon CD1d, a MHC-class I-type molecule that presents lipids, especially glycolipids to the T cell receptors on NKT cells. There are two classes of NKT cells; invariant NKT cells that express a semi-invariant T cell receptor and variant NKT cells. This review summarises studies in murine models in which the effect of the activation, overexpression or deletion of NKT cells or only invariant NKT cells on atherosclerosis has been examined.

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Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells

Journal of Experimental Medicine ◽

10.1084/jem.20130958 ◽

2013 ◽

Vol 210 (11) ◽

pp. 2305-2320 ◽

Cited By ~ 317

Author(s):

Rangsima Reantragoon ◽

Alexandra J. Corbett ◽

Isaac G. Sakala ◽

Nicholas A. Gherardin ◽

John B. Furness ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Biology ◽

Cell Receptor ◽

Phenotypic Characterization ◽

Mait Cells ◽

Invariant T Cells ◽

Human And Mouse ◽

Mait Cell

Mucosal-associated invariant T cells (MAIT cells) express a semi-invariant T cell receptor (TCR) α-chain, TRAV1-2–TRAJ33, and are activated by vitamin B metabolites bound by the major histocompatibility complex (MHC)–related class I–like molecule, MR1. Understanding MAIT cell biology has been restrained by the lack of reagents to specifically identify and characterize these cells. Furthermore, the use of surrogate markers may misrepresent the MAIT cell population. We show that modified human MR1 tetramers loaded with the potent MAIT cell ligand, reduced 6-hydroxymethyl-8-d-ribityllumazine (rRL-6-CH2OH), specifically detect all human MAIT cells. Tetramer+ MAIT subsets were predominantly CD8+ or CD4−CD8−, although a small subset of CD4+ MAIT cells was also detected. Notably, most human CD8+ MAIT cells were CD8α+CD8β−/lo, implying predominant expression of CD8αα homodimers. Tetramer-sorted MAIT cells displayed a TH1 cytokine phenotype upon antigen-specific activation. Similarly, mouse MR1–rRL-6-CH2OH tetramers detected CD4+, CD4−CD8− and CD8+ MAIT cells in Vα19 transgenic mice. Both human and mouse MAIT cells expressed a broad TCR-β repertoire, and although the majority of human MAIT cells expressed TRAV1-2–TRAJ33, some expressed TRAJ12 or TRAJ20 genes in conjunction with TRAV1-2. Accordingly, MR1 tetramers allow precise phenotypic characterization of human and mouse MAIT cells and revealed unanticipated TCR heterogeneity in this population.

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Dual TCR-alpha expression on MAIT cells as a potential confounder of TCR interpretation

10.1101/2021.03.25.436871 ◽

2021 ◽

Author(s):

Sara Suliman ◽

Lars Kjer-Nielsen ◽

Sarah K. Iwany ◽

Kattya Lopez Tamara ◽

Liyen Loh ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Single Cell ◽

Cell Receptor ◽

Antigen Specificity ◽

Mait Cells ◽

Human T Cells ◽

V Genes ◽

Antigen Presenting ◽

Β Chain

AbstractMucosal-associated invariant T (MAIT) cells are innate-like T cells that are highly abundant in human blood and tissues. Most MAIT cells have an invariant T cell receptor (TCR) α chain that uses TRAV1-2 joined to TRAJ33/20/12 and recognize metabolites from bacterial riboflavin synthesis bound to the antigen-presenting molecule, MR1. Recently, our attempts to identify alternative MR1-presented antigens led to the discovery of rare MR1-restricted T cells with non-TRAV1-2 TCRs. Because altered antigen specificity is likely to lead to altered affinity for the most potent known antigen, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), we performed bulk TCRα and β chain sequencing, and single cell-based paired TCR sequencing, on T cells that bound the MR1-5-OP-RU tetramer, but with differing intensities. Bulk sequencing showed that use of V genes other than TRAV1-2 was enriched among MR1-5-OP-RU tetramerlow cells. Whereas we initially interpreted these as diverse MR1-restricted TCRs, single cell TCR sequencing revealed that cells expressing atypical TCRα chains also co-expressed an invariant MAIT TCRα chain. Transfection of each non-TRAV1-2 TCRα chain with the TCRβ chain from the same cell demonstrated that the non-TRAV1-2 TCR did not bind the MR1-5-OP-RU tetramer. Thus, dual TCRα chain expression in human T cells and competition for the endogenous β chain explains the existence of some MR1-5-OP-RU tetramerlow T cells. The discovery of simultaneous expression of canonical and non-canonical TCRs on the same T cell means that claims of roles for non-TRAV1-2 TCR in MR1 response must be validated by TCR transfer-based confirmation of antigen specificity.

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Clonotype pattern in T-cell lymphomas map the cell of origin to immature lymphoid precursors

Blood Advances ◽

10.1182/bloodadvances.2021005884 ◽

2022 ◽

Author(s):

Aishwarya Iyer ◽

Dylan Christopher Hennessey ◽

Robert Gniadecki

Keyword(s):

T Cells ◽

T Cell ◽

De Novo ◽

Cell Lymphoma ◽

Large Cell ◽

Cell Receptor ◽

Cell Of Origin ◽

Sequencing Data ◽

T Cell Lymphomas ◽

Complementarity Determining Regions

Mature T-cell lymphomas (TCLs) are rare, clinically heterogeneous hematologic cancers of high medical need. TCLs have inferior prognosis which is attributed to poor understanding of their pathogenesis. Based on phenotypic similarities between normal and neoplastic lymphocytes it has been assumed that TCLs develop in the periphery, directly from various subtypes of normal T-cells. To address the debated question of the cell of origin in TCLs we analyzed to identify the highly variable complementarity determining regions (CDR3) regions of T-cell receptor (TCR) to trace the clonal history of the T-cells. We have collected previously published whole genome -exome, and -transcriptome sequencing data from 574 TCL patients. TCR clonotypes were identified by de novo assembly of CDR3 regions of TCR γ, β and α. We have found that the vast majority of TCLs are clonotypically oligoclonal, although the pattern oligoclonality varied. Anaplastic large cell lymphoma was most diverse comprising multiple clonotypes of TCRγ, β and α whereas adult T-cell lymphoma/leukemia and peripheral T-cell lymphomas often showed monoclonality for TCRγ and β but had diverse TCRα clonotypes. These patterns of rearrangements indicated that TCLs are initiated at the level of the lymphoid precursor. In keeping with this hypothesis, TCR rearrangements in TCLs resembled the pattern seen in the human thymus showing biased usage of V and J segments of high combinatorial probability resulting in recurrent, "public" CDR3 sequences shared across unrelated patients and different clinical TCL entities. Clonotypically diverse initiating cells may seed target tissues being responsible for disease relapses after therapy.

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How Antigen Quantity and Quality Determine T-Cell Decisions in Lymphoid Tissue

Molecular and Cellular Biology ◽

10.1128/mcb.00136-08 ◽

2008 ◽

Vol 28 (12) ◽

pp. 4040-4051 ◽

Cited By ~ 46

Author(s):

Huan Zheng ◽

Bo Jin ◽

Sarah E. Henrickson ◽

Alan S. Perelson ◽

Ulrich H. von Andrian ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Receptor ◽

Antigen Dose ◽

Binding Characteristics ◽

Mhc Genes ◽

Antigenic Proteins ◽

Future Experimentation ◽

Time Required ◽

Antigen Presenting

ABSTRACT T lymphocytes (T cells) express T-cell receptor (TCR) molecules on their surface that can recognize peptides (p) derived from antigenic proteins bound to products of the major histocompatibility complex (MHC) genes. The pMHC molecules are expressed on the surface of antigen-presenting cells, such as dendritic cells (DCs). T cells first encounter antigen on DCs in lymph nodes (LN). Intravital microscopy experiments show that upon entering the LN containing antigen, CD8+ T cells first move rapidly. After a few hours, they stop and make extended contacts with DCs. The factors that determine when and how this transition occurs are not well understood. We report results from computer simulations that suggest that the duration of phase one is related to the low probability of productive interactions between T cells and DCs. This is demonstrated by our finding that the antigen dose and type determine when such a transition occurs. These results are in agreement with experimental observations. TCR-pMHC binding characteristics and the antigen dose determine the time required for a productive T-cell-DC encounter (resulting in sustained contact). We find that the ratio of this time scale and the half-life of the pMHC complex itself provide a consolidated measure of antigen quantity and type. Results obtained upon varying different measures of antigen quantity and type fall on one curve when graphed against this ratio of time scales. Thus, we provide a mechanism for how the effects of varying one set of parameters are influenced by other prevailing conditions. This understanding should help guide future experimentation.

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