scholarly journals Somatic genetics of CDR3 control TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

2021 ◽  
Author(s):  
Joseph Murray
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Genetic Linkage ◽  
Alpha Helix ◽  
Volumetric Density ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Hla Dr ◽  
Hla Dq ◽  
Relative Affinity

Abstract The mechanism which adapts the T-cell antigen receptor (TCR) within a given major histocompatibility complex (MHC/HLA) genotype is essential for protection against pathogens. Historically attributed to relative affinity, genetically vast TCRs are surprisingly focused towards a micromolar affinity for their respective peptide (p) plus MHC (pMHC) ligands. Thus, the somatic diversity of the TCR with respect to MHC-restriction, and (ultimately) to pathogens, remains enigmatic. Here, we derive a triple integral solution (from fixed geometry) for any given V domain in TCR bound to pMHC. Solved complexes involving HLA-DR and HLA-DQ, where genetic linkage to the TCR is most profound, were examined in detail. Certain V domains displayed rare geometry within this panel—specifying a restricted rotational probability/volumetric density (dV). Remarkably, hydrogen (H) bond charge-relays distinguished these structures from the others; suggesting that CDR3 binding chemistry dictates CDR2 contacts on the opposite MHC-II alpha helix. Together, these data suggest that TCR recapitulate dV and specialise target pMHC recognition, i.e., a dynamics alternative to a relative TCR-affinity based mechanism.

scholarly journals Somatic genetics of CDR3 control TCR V-domain rotational probability effecting germline CDR2 scanning of polymorphic MHC

2019 ◽  
Author(s):  
Joseph S. Murray
Keyword(s):  
Integral Equation ◽  
Genetic Linkage ◽  
Alpha Helix ◽  
Volumetric Density ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Hla Dr ◽  
Hla Dq ◽  
Relative Affinity ◽  
Triple Integral Equation

AbstractThe mechanism which adapts the T-cell antigen receptor (TCR) within a given major histocompatibility complex (MHC; HLA, in humans) genotype is essential for protection against pathogens. Historically attributed to relative affinity, genetically vast TCRs are surprisingly focused towards a micromolar affinity for their respective peptide (p) plus MHC (pMHC) ligands. Thus, the somatic diversity of the TCR with respect to MHC restriction, and (ultimately) to pathogens, remains enigmatic. Here, we derive a triple integral equation (from fixed geometry) for any given V-domain in TCR bound to pMHC. We examine solved complexes involving HLA-DR and HLA-DQ, where genetic linkage to the TCR is most profound. Certain V-beta domains displayed rare geometry within this panel—specifying a very low (highly-restricted) rotational probability/volumetric density (dV). Remarkably, hydrogen (H)-bond charge-relays distinguished these structures from the others; suggesting that CDR3 binding chemistry dictates CDR2 contacts on the respective MHC-II alpha-helix.

scholarly journals The Major Histocompatibility Complex Class II Alleles Mamu-DRB1*1003 and -DRB1*0306 Are Enriched in a Cohort of Simian Immunodeficiency Virus-Infected Rhesus Macaque Elite Controllers

2007 ◽  
Vol 82 (2) ◽  
pp. 859-870 ◽  
Author(s):  
Juan P. Giraldo-Vela ◽  
Richard Rudersdorf ◽  
Chungwon Chung ◽  
Ying Qi ◽  
Lyle T. Wallace ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Viral Replication ◽  
Rhesus Macaques ◽  
Complex Class ◽  
Elite Controllers ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus

ABSTRACT The role of CD4+ T cells in the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication is not well understood. Even though strong HIV- and SIV-specific CD4+ T-cell responses have been detected in individuals that control viral replication, major histocompatibility complex class II (MHC-II) molecules have not been definitively linked with slow disease progression. In a cohort of 196 SIVmac239-infected Indian rhesus macaques, a group of macaques controlled viral replication to less than 1,000 viral RNA copies/ml. These elite controllers (ECs) mounted a broad SIV-specific CD4+ T-cell response. Here, we describe five macaque MHC-II alleles (Mamu-DRB*w606, -DRB*w2104, -DRB1*0306, -DRB1*1003, and -DPB1*06) that restricted six SIV-specific CD4+ T-cell epitopes in ECs and report the first association between specific MHC-II alleles and elite control. Interestingly, the macaque MHC-II alleles, Mamu-DRB1*1003 and -DRB1*0306, were enriched in this EC group (P values of 0.02 and 0.05, respectively). Additionally, Mamu-B*17-positive SIV-infected rhesus macaques that also expressed these two MHC-II alleles had significantly lower viral loads than Mamu-B*17-positive animals that did not express Mamu-DRB1*1003 and -DRB1*0306 (P value of <0.0001). The study of MHC-II alleles in macaques that control viral replication could improve our understanding of the role of CD4+ T cells in suppressing HIV/SIV replication and further our understanding of HIV vaccine design.

scholarly journals Mycobacterium tuberculosis Synergizes with ATP To Induce Release of Microvesicles and Exosomes Containing Major Histocompatibility Complex Class II Molecules Capable of Antigen Presentation

2010 ◽  
Vol 78 (12) ◽  
pp. 5116-5125 ◽  
Author(s):  
Lakshmi Ramachandra ◽  
Yan Qu ◽  
Ying Wang ◽  
Colleen J. Lewis ◽  
Brian A. Cobb ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Major Histocompatibility Complex Class ◽  
Class Ii ◽  
Hybridoma Cells ◽  
Complex Class ◽  
Mhc Ii ◽  
Histocompatibility Complex

ABSTRACT Major histocompatibility complex class II (MHC-II) molecules are released by murine macrophages upon lipopolysaccharide (LPS) stimulation and ATP signaling through the P2X7 receptor. These studies show that infection of macrophages with Mycobacterium tuberculosis or M. bovis strain BCG enhances MHC-II release in synergy with ATP. Shed MHC-II was contained in two distinct organelles, exosomes and plasma membrane-derived microvesicles, which were both able to present exogenous antigenic peptide to T hybridoma cells. Furthermore, microvesicles from mycobacterium-infected macrophages were able to directly present M. tuberculosis antigen (Ag) 85B(241-256)-I-Ab complexes that were generated by the processing of M. tuberculosis Ag 85B in infected cells to both M. tuberculosis-specific T hybridoma cells and naïve P25 M. tuberculosis T-cell receptor (TCR)-transgenic T cells. In the presence of prefixed macrophages, exosomes from mycobacterium-infected macrophages provided weak stimulation to M. tuberculosis-specific T hybridoma cells but not naïve P25 T cells. Thus, infection with M. tuberculosis primes macrophages for the increased release of exosomes and microvesicles bearing M. tuberculosis peptide-MHC-II complexes that may generate antimicrobial T-cell responses.

Functional interaction between human T-cell protein CD4 and the major histocompatibility complex HLA-DR antigen

Nature ◽  
1987 ◽  
Vol 328 (6131) ◽  
pp. 626-629 ◽  
Author(s):  
Denise Gay ◽  
Paul Maddon ◽  
Rafick Sekaly ◽  
Mary Anne Talle ◽  
Maurice Godfrey ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Cell Protein ◽  
Major Histocompatibility ◽  
Functional Interaction ◽  
Histocompatibility Complex ◽  
Human T Cell ◽  
Hla Dr

scholarly journals CD9 Regulates Major Histocompatibility Complex Class II Trafficking in Monocyte-Derived Dendritic Cells

2017 ◽  
Vol 37 (15) ◽  
Author(s):  
Vera Rocha-Perugini ◽  
Gloria Martínez del Hoyo ◽  
José María González-Granado ◽  
Marta Ramírez-Huesca ◽  
Virginia Zorita ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Complex Class ◽  
Gm Csf ◽  
Mhc Ii ◽  
Histocompatibility Complex

ABSTRACT Antigen presentation by dendritic cells (DCs) stimulates naive CD4+ T cells, triggering T cell activation and the adaptive arm of the immune response. Newly synthesized major histocompatibility complex class II (MHC-II) molecules accumulate at MHC-II-enriched endosomal compartments and are transported to the plasma membrane of DCs after binding to antigenic peptides to enable antigen presentation. In DCs, MHC-II molecules are included in tetraspanin-enriched microdomains (TEMs). However, the role of tetraspanin CD9 in these processes remains largely undefined. Here, we show that CD9 regulates the T cell-stimulatory capacity of granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent bone marrow-derived DCs (BMDCs), without affecting antigen presentation by fms-like tyrosine kinase 3 ligand (Flt3L)-dependent BMDCs. CD9 knockout (KO) GM-CSF-dependent BMDCs, which resemble monocyte-derived DCs (MoDCs), induce lower levels of T cell activation than wild-type DCs, and this effect is related to a reduction in MHC-II surface expression in CD9-deficient MoDCs. Importantly, MHC-II targeting to the plasma membrane is largely impaired in immature CD9 KO MoDCs, in which MHC-II remains arrested in acidic intracellular compartments enriched in LAMP-1 (lysosome-associated membrane protein 1), and MHC-II internalization is also blocked. Moreover, CD9 participates in MHC-II trafficking in mature MoDCs, regulating its endocytosis and recycling. Our results demonstrate that the tetraspanin CD9 specifically regulates antigenic presentation in MoDCs through the regulation of MHC-II intracellular trafficking.

scholarly journals Inhibition of HLA-DR Assembly, Transport, and Loading by Human Cytomegalovirus Glycoprotein US3: a Novel Mechanism for Evading Major Histocompatibility Complex Class II Antigen Presentation

2002 ◽  
Vol 76 (21) ◽  
pp. 10929-10941 ◽  
Author(s):  
Nagendra R. Hegde ◽  
Roman A. Tomazin ◽  
Todd W. Wisner ◽  
Claire Dunn ◽  
Jessica M. Boname ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Antigen Presentation ◽  
Class Ii ◽  
Complex Class ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Hla Dr ◽  
Antigen Presentation Pathway ◽  
Presentation Pathway

ABSTRACT Human cytomegalovirus (HCMV) establishes persistent lifelong infections and replicates slowly. To withstand robust immunity, HCMV utilizes numerous immune evasion strategies. The HCMV gene cassette encoding US2 to US11 encodes four homologous glycoproteins, US2, US3, US6, and US11, that inhibit the major histocompatibility complex class I (MHC-I) antigen presentation pathway, probably inhibiting recognition by CD8+ T lymphocytes. US2 also inhibits the MHC-II antigen presentation pathway, causing degradation of human leukocyte antigen (HLA)-DR-α and -DM-α and preventing recognition by CD4+ T cells. We investigated the effects of seven of the US2 to US11 glycoproteins on the MHC-II pathway. Each of the glycoproteins was expressed by using replication-defective adenovirus vectors. In addition to US2, US3 inhibited recognition of antigen by CD4+ T cells by a novel mechanism. US3 bound to class II α/β complexes in the endoplasmic reticulum (ER), reducing their association with Ii. Class II molecules moved normally from the ER to the Golgi apparatus in US3-expressing cells but were not sorted efficiently to the class II loading compartment. As a consequence, formation of peptide-loaded class II complexes was reduced. We concluded that US3 and US2 can collaborate to inhibit class II-mediated presentation of endogenous HCMV antigens to CD4+ T cells, allowing virus-infected cells to resist recognition by CD4+ T cells.

scholarly journals The V beta complementarity determining region 1 of a major histocompatibility complex (MHC) class I-restricted T cell receptor is involved in the recognition of peptide/MHC I and superantigen/MHC II complex.

1994 ◽  
Vol 179 (4) ◽  
pp. 1087-1097 ◽  
Author(s):  
M Bellio ◽  
Y C Lone ◽  
O de la Calle-Martin ◽  
B Malissen ◽  
J P Abastado ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class I ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Class I ◽  
Mhc I ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Complementarity Determining Region

We investigated the role of the complementarity determining region 1 (CDR1) of T cell receptor (TCR) beta chain both in antigen/major histocompatibility complex I (MHC I) and in superantigen (SAg)/MHC II complex recognition. Residues 26 to 31 of the V beta 10 domain of a TCR derived from an H-2Kd-restricted cytotoxic clone were individually changed to alanine, using site-directed mutagenesis, and the mutated TCR beta chains were transfected along with the wild-type TCR alpha chain into a TCR alpha-beta-T hydridoma. These mutations affected antigen/H-2Kd complex recognition, although to a different extent, as estimated by interleukin 2 production. Certain mutations also affected differently the recognition of two Staphylococcal toxins, exfoliative toxin and Staphylococcal enterotoxin C2, presented by HLA-DR1. Whereas mutation of residues D30 or T31 affect the recognition of both toxins, residues T26, L27, and H29 are critical for the recognition of only one of the SAgs. These observations demonstrate the participation of the CDR1 region in the recognition of peptide/MHC class I as well as SAg/MHC II complexes.

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