scholarly journals Inherent reactivity of unselected TCR repertoires to peptide-MHC molecules

2019 ◽  
Vol 116 (44) ◽  
pp. 22252-22261 ◽  
Author(s):  
S. Harsha Krovi ◽  
John W. Kappler ◽  
Philippa Marrack ◽  
Laurent Gapin
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Selective Pressure ◽  
Dominant Role ◽  
Antigen Receptors ◽  
Complex Molecules ◽  
Peptide Antigens ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Antigen Presenting

The repertoire of αβ T cell antigen receptors (TCRs) on mature T cells is selected in the thymus where it is rendered both self-tolerant and restricted to the recognition of major histocompatibility complex molecules presenting peptide antigens (pMHC). It remains unclear whether germline TCR sequences exhibit an inherent bias to interact with pMHC prior to selection. Here, we isolated TCR libraries from unselected thymocytes and upon reexpression of these random TCR repertoires in recipient T cell hybridomas, interrogated their reactivities to antigen-presenting cell lines. While these random TCR combinations could potentially have reacted with any surface molecule on the cell lines, the hybridomas were stimulated most frequently by pMHC ligands. The nature and CDR3 loop composition of the TCRβ chain played a dominant role in determining pMHC-reactivity. Replacing the germline regions of mouse TCRβ chains with those of other jawed vertebrates preserved reactivity to mouse pMHC. Finally, introducing the CD4 coreceptor into the hybridomas increased the proportion of cells that could respond to pMHC ligands. Thus, αβ TCRs display an intrinsic and evolutionary conserved bias for pMHC molecules in the absence of any selective pressure, which is further strengthened in the presence of coreceptors.

scholarly journals The Role of Peptides in T Cell Alloreactivity Is Determined by Self–Major Histocompatibility Complex Molecules

2000 ◽  
Vol 191 (5) ◽  
pp. 805-812 ◽  
Author(s):  
Reinhard Obst ◽  
Nikolai Netuschil ◽  
Karsten Klopfer ◽  
Stefan Stevanović ◽  
Hans-Georg Rammensee
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Target Cells ◽  
Major Histocompatibility ◽  
Complex Molecules ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Alloreactive T Cells

By analyzing T cell responses against foreign major histocompatibility complex (MHC) molecules loaded with peptide libraries and defined self- and viral peptides, we demonstrate a profound influence of self-MHC molecules on the repertoire of alloreactive T cells: the closer the foreign MHC molecule is related to the T cell's MHC, the higher is the proportion of peptide-specific, alloreactive (“allorestricted”) T cells versus T cells recognizing the foreign MHC molecule without regard to the peptide in the groove. Thus, the peptide repertoire of alloreactive T cells must be influenced by self-MHC molecules during positive or negative thymic selection or peripheral survival, much like the repertoire of the self-restricted T cells. In consequence, allorestricted, peptide-specific T cells (that are of interest for clinical applications) are easier to obtain if T cells and target cells express related MHC molecules.

scholarly journals T cells specific for alpha-beta interface regions of hemoglobin recognize the isolated subunit but not the tetramer and indicate presentation without processing

1989 ◽  
Vol 86 (17) ◽  
pp. 6729-6733 ◽  
Author(s):  
M Z Atassi ◽  
M Yoshioka ◽  
G S Bixler
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Cell Lines ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Oligomeric Protein ◽  
T Cell Lines ◽  
Antigen Presenting

Processing of a protein antigen into fragments is believed to be a prerequisite for its presentation by the antigen-presenting cell to the T cell. This model would predict that, in oligomeric proteins, T cells prepared with specificity for regions that are buried within subunit association surfaces should recognize the respective regions in vitro equally well on the isolated subunit or on the oligomer. Three hemoglobin (Hb) alpha-chain synthetic peptides, corresponding to areas that are situated either completely [alpha-(31-45)] or partially [alpha-(41-45) and alpha-(81-95)] within the interface between the alpha and beta subunits of Hb, and a fourth peptide representing a completely exposed area in tetrameric Hb were used as immunogens in SJL/J (H-2s) mice. Peptide-primed T cells were passaged in vitro with the respective peptide to obtain peptide-specific T-lymphocyte lines. T-cell clones were isolated from these lines by limiting dilution. T-cell lines and clones that were specific for buried regions in the subunit association surfaces recognized the free peptide and the isolated subunit but not the Hb tetramer. On the other hand, T cells with specificity against regions that are not involved in subunit interaction and are completely exposed in the tetramer recognized the peptide, the isolated subunit, and the oligomeric protein equally well. The responses of the T-cell lines and clones were major histocompatibility complex-restricted. Since the same x-irradiated antigen-presenting cells were employed, the results could not be attributed to differences or defects in Hb processing. The findings indicate that in vitro the native (unprocessed and undissociated) oligomeric protein was the trigger of major histocompatibility complex-restricted T-cell responses.

scholarly journals Endogenous and Exogenous CD1-Binding Glycolipids

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Janice M. H. Cheng ◽  
Ashna A. Khan ◽  
Mattie S. M. Timmer ◽  
Bridget L. Stocker
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Intracellular Trafficking ◽  
Antigen Presenting Cells ◽  
Peptide Antigens ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Antigen Presenting

In the same way that peptide antigens are presented by major histocompatibility complex (MHC) molecules, glycolipid antigens can also activate the immune response via binding to CD1 proteins on antigen-presenting cells (APCs) and stimulate CD1-restricted T cells. In humans, there are five members of the CD1 family, termed CD1a–e, of which CD1a–d are involved in glycolipid presentation at the cell surface, while CD1e is involved in the intracellular trafficking of glycolipid antigens. Both endogenous (self-derived) and exogenous (non-self-derived) glycolipids have been shown to bind to members of the CD1 family with varying degrees of specificity. In this paper we focus on the key glycolipids that bind to the different members of the CD1 family.

scholarly journals Role of BoLA-DRB3 genetic diversity against resistance to mastitis in cattle: Review

2019 ◽  
pp. 30-36 ◽  
Author(s):  
Namita Kumari ◽  
Shubham Loat ◽  
Shallu Saini ◽  
Nitika Dhilor ◽  
Anurag Kumar ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Immune Response ◽  
Major Histocompatibility Complex ◽  
Immune Regulation ◽  
Peptide Antigens ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Antigen Presenting ◽  
Jawless Fish

The major histocompatibility complex (MHC) is an organized cluster of tightly linked genes, present in all vertebrates, playing an important role in the immune system, except the jawless fish [1]. MHC was first identified during tissue transplantation studies in mice [2] and was first known for its role in histocompatibility. Consequently, the role of MHC was discovered in immune regulation [3] and several other functions [4,5]. The important function of the MHC is to code for specialized antigen-presenting receptor glycoproteins, also called as MHC molecules. The products of these genes are involved in the induction and regulation of immune response. These molecules bind processed peptide antigens and present them to T-lymphocytes, thereby triggering immune response.

scholarly journals Self tolerance to T cell receptor V beta sequences.

1995 ◽  
Vol 182 (1) ◽  
pp. 249-254 ◽  
Author(s):  
F Falcioni ◽  
D Vidović ◽  
E S Ward ◽  
D Bolin ◽  
G Singh ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Hypervariable Region ◽  
Cell Receptor ◽  
T Cell Tolerance ◽  
Antigen Receptors ◽  
Complex Molecules ◽  
Histocompatibility Complex ◽  
Self Tolerance ◽  
Beta Peptide

T cell tolerance to self is achieved by deletion or inactivation of clones recognizing peptides of self proteins presented by major histocompatibility complex molecules. A considerable fraction of self proteins accessible to the immune system is contributed by the system itself, for example, the receptors used for antigen recognition (antibodies and T cell receptors [TCRs]). Thus far, it has remained unclear, whether antigen receptors are subject to self tolerance, or on contrary, engage into network interactions implying immunity rather than tolerance. In this study, we demonstrate self tolerance to synthetic peptides corresponding to the first hypervariable region of the V beta 8.1 and V beta 8.2 TCR proteins. We also show that the tolerogenic synthetic peptide corresponds to a fragment produced by processing of the V beta protein, and conversely, that a V beta peptide not produced by processing is also not subject to self tolerance. Thus, the rules of tolerance seem to apply to antigen receptors, at least to their germline-encoded portions, in a similar fashion as to other self proteins. This finding has important implications for studies of natural and artificially induced immune networks.

scholarly journals Molecular Recognition of Lipid Antigens by T Cell Receptors

1999 ◽  
Vol 189 (1) ◽  
pp. 195-205 ◽  
Author(s):  
Ethan P. Grant ◽  
Massimo Degano ◽  
Jean-Pierre Rosat ◽  
Steffen Stenger ◽  
Robert L. Modlin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Antigen Specificity ◽  
Peptide Antigen ◽  
Lipid Antigens ◽  
Peptide Antigens ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Lipid Antigen ◽  
Binding Groove

The T cell antigen receptor (TCR) mediates recognition of peptide antigens bound in the groove of major histocompatibility complex (MHC) molecules. This dual recognition is mediated by the complementarity-determining residue (CDR) loops of the α and β chains of a single TCR which contact exposed residues of the peptide antigen and amino acids along the MHC α helices. The recent description of T cells that recognize hydrophobic microbial lipid antigens has challenged immunologists to explain, in molecular terms, the nature of this interaction. Structural studies on the murine CD1d1 molecule revealed an electrostatically neutral putative antigen-binding groove beneath the CD1 α helices. Here, we demonstrate that α/β TCRs, when transferred into TCR-deficient recipient cells, confer specificity for both the foreign lipid antigen and CD1 isoform. Sequence analysis of a panel of CD1-restricted, lipid-specific TCRs reveals the incorporation of template-independent N nucleotides that encode diverse sequences and frequent charged basic residues at the V(D)J junctions. These sequences permit a model for recognition in which the TCR CDR3 loops containing charged residues project between the CD1 α helices, contacting the lipid antigen hydrophilic head moieties as well as adjacent CD1 residues in a manner that explains antigen specificity and CD1 restriction.

scholarly journals Major histocompatibility complex conformational epitopes are peptide specific.

1992 ◽  
Vol 176 (6) ◽  
pp. 1611-1618 ◽  
Author(s):  
B Catipović ◽  
J Dal Porto ◽  
M Mage ◽  
T E Johansen ◽  
J P Schneck
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Murine Cytomegalovirus ◽  
Major Histocompatibility ◽  
Cell Repertoire ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Derivatives Of

Serologically distinct forms of H-2Kb are stabilized by loading cells expressing "empty" class I major histocompatibility complex (MHC) molecules with different H-2Kb binding peptides. The H-2Kb epitope recognized by monoclonal antibody (mAb) 28.8.6 was stabilized by ovalbumin (OVA) (257-264) and murine cytomegalovirus (MCMV) pp89 (168-176) peptides, but not by vesicular stomatic virus nucleoprotein (VSV NP) (52-59) and influenza NP (Y345-360) peptides. The H-2Kb epitope recognized by mAb 34.4.20 was stabilized by VSV NP (52-59) peptide but not by OVA (257-264), MCMV pp89 (168-176), or influenza NP (Y345-360) peptides. Immunoprecipitation of H-2Kb molecules from normal cells showed that 28.8.6 and 34.4.20 epitopes were only present on a subset of all conformationally reactive H-2Kb molecules. Using alanine-substituted derivatives of the VSV peptide, the 28.8.6 epitope was completely stabilized by substitution of the first residue and partially stabilized by substitution of the third or the fifth residues in the peptides. These results indicate that distinct conformational MHC epitopes are dependent on the specific peptide that occupies the antigenic peptide binding groove on individual MHC molecules. The changes in MHC epitopes observed may also be important in understanding the diversity of T cell receptors used in an immune response and the influence of peptides on development of the T cell repertoire.

scholarly journals An HLA-A2-restricted tyrosinase antigen on melanoma cells results from posttranslational modification and suggests a novel pathway for processing of membrane proteins.

1996 ◽  
Vol 183 (2) ◽  
pp. 527-534 ◽  
Author(s):  
J C Skipper ◽  
R C Hendrickson ◽  
P H Gulden ◽  
V Brichard ◽  
A Van Pel ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Melanoma Cells ◽  
Amino Acid Sequences ◽  
Class I ◽  
Antigenic Peptides ◽  
Peptide Antigens ◽  
Mhc Molecules ◽  
Tyrosinase Gene ◽  
Histocompatibility Complex ◽  
Natural Peptide

T lymphocytes recognize antigens consisting of peptides presented by class I and II major histocompatibility complex (MHC) molecules. The peptides identified so far have been predictable from the amino acid sequences of proteins. We have identified the natural peptide target of a CTL clone that recognizes the tyrosinase gene product on melanoma cells. The peptide results from posttranslational conversion of asparagine to aspartic acid. This change is of central importance for peptide recognition by melanoma-specific T cells, but has no impact on peptide binding to the MHC molecule. This posttranslational modification has not been previously described for any MHC-associated peptide and represents the first demonstration of posttranslational modification of a naturally processed class I-associated peptide. This observation is relevant to the identification and prediction of potential peptide antigens. The most likely mechanism for production of this peptide leads to the suggestion that antigenic peptides can be derived from proteins that are translated into the endoplasmic reticulum.

scholarly journals Human TCR-MHC coevolution after divergence from mice includes increased nontemplate-encoded CDR3 diversity

2017 ◽  
Vol 214 (11) ◽  
pp. 3417-3433 ◽  
Author(s):  
Xiaojing Chen ◽  
Lucia Poncette ◽  
Thomas Blankenstein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Mhc Molecules ◽  
Mhc Ii ◽  
Cdr3 Length ◽  
Tcr Repertoire ◽  
Cell Diversity ◽  
Antigen Presenting

For thymic selection and responses to pathogens, T cells interact through their αβ T cell receptor (TCR) with peptide–major histocompatibility complex (MHC) molecules on antigen-presenting cells. How the diverse TCRs interact with a multitude of MHC molecules is unresolved. It is also unclear how humans generate larger TCR repertoires than mice do. We compared the TCR repertoire of CD4 T cells selected from a single mouse or human MHC class II (MHC II) in mice containing the human TCR gene loci. Human MHC II yielded greater thymic output and a more diverse TCR repertoire. The complementarity determining region 3 (CDR3) length adjusted for different inherent V-segment affinities to MHC II. Humans evolved with greater nontemplate-encoded CDR3 diversity than did mice. Our data, which demonstrate human TCR–MHC coevolution after divergence from rodents, explain the greater T cell diversity in humans and suggest a mechanism for ensuring that any V–J gene combination can be selected by a single MHC II.

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