scholarly journals Recognition of the Major Histocompatibility Complex Restriction Element Modulates CD8+ T Cell Specificity and Compensates for Loss of  T Cell Receptor Contacts with the Specific Peptide

1999 ◽  
Vol 189 (6) ◽  
pp. 883-894 ◽  
Author(s):  
Johan K. Sandberg ◽  
Klas Kärre ◽  
Rickard Glas
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Peptide Ligand ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Cell Specificity ◽  
Restriction Element

Triggering of a T cell requires interaction between its specific receptor (TCR) and a peptide antigen presented by a self–major histocompatibility complex (MHC) molecule. TCR recognition of self-MHC by itself falls below the threshold of detection in most systems due to low affinity. To study this interaction, we have used a read-out system in which antigen-specific effector T cells are confronted with targets expressing high levels of MHC compared with the selecting and priming environment. More specifically, the system is based on CD8+ T cells selected in an environment with subnormal levels of MHC class I in the absence of β2-microglobulin. We observe that the MHC restriction element can trigger viral peptide-specific T cells independently of the peptide ligand, provided there is an increase in self-MHC density. Peptide-independent triggering required at least four times the natural in vivo level of MHC expression. Furthermore, recognition of the restriction element at expression levels below this threshold was still enough to compensate for lack of affinity to peptides carrying alanine substitutions in major TCR contact residues. Thus, the specificity in TCR recognition and T cell activation is fine tuned by the avidity for self-MHC, and TCR avidities for peptide and MHC may substitute for each other. These results demonstrate a functional role for TCR avidity for self-MHC in tuning of T cell specificity, and support a role for cross-reactivity on “self” during T cell selection and activation.

scholarly journals Potent T Cell Activation with Dimeric Peptide–Major Histocompatibility Complex Class II Ligand: The Role of CD4 Coreceptor

1998 ◽  
Vol 188 (9) ◽  
pp. 1633-1640 ◽  
Author(s):  
Abdel Rahim A. Hamad ◽  
Sean M. O'Herrin ◽  
Michael S. Lebowitz ◽  
Ananth Srikrishnan ◽  
Joan Bieler ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

The interaction of the T cell receptor (TCR) with its cognate peptide–major histocompatibility complex (MHC) on the surface of antigen presenting cells (APCs) is a primary event during T cell activation. Here we used a dimeric IEk-MCC molecule to study its capacity to activate antigen-specific T cells and to directly analyze the role of CD4 in physically stabilizing the TCR–MHC interaction. Dimeric IEk-MCC stably binds to specific T cells. In addition, immobilized dimeric IEk-MCC can induce TCR downregulation and activate antigen-specific T cells more efficiently than anti-CD3. The potency of the dimeric IEk-MCC is significantly enhanced in the presence of CD4. However, CD4 does not play any significant role in stabilizing peptide-MHC–TCR interactions as it fails to enhance binding of IEk-MCC to specific T cells or influence peptide-MHC–TCR dissociation rate or TCR downregulation. Moreover, these results indicate that dimerization of peptide-MHC class II using an IgG molecular scaffold significantly increases its binding avidity leading to an enhancement of its stimulatory capacity while maintaining the physiological properties of cognate peptide–MHC complex. These peptide-MHC–IgG chimeras may, therefore, provide a novel approach to modulate antigen-specific T cell responses both in vitro and in vivo.

scholarly journals Modified Vaccinia Virus Ankara-Infected Dendritic Cells Present CD4+T-Cell Epitopes by Endogenous Major Histocompatibility Complex Class II Presentation Pathways

2014 ◽  
Vol 89 (5) ◽  
pp. 2698-2709 ◽  
Author(s):  
Frank Thiele ◽  
Sha Tao ◽  
Yi Zhang ◽  
Andreas Muschaweckh ◽  
Tina Zollmann ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Vaccinia Virus ◽  
T Cell Activation ◽  
Antigen Processing ◽  
Cell Activation ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Modified Vaccinia Virus Ankara

ABSTRACTCD4+T lymphocytes play a central role in the immune system and mediate their function after recognition of their respective antigens presented on major histocompatibility complex II (MHCII) molecules on antigen-presenting cells (APCs). Conventionally, phagocytosed antigens are loaded on MHCII for stimulation of CD4+T cells. Certain epitopes, however, can be processed directly from intracellular antigens and are presented on MHCII (endogenous MHCII presentation). Here we characterized the MHCII antigen presentation pathways that are possibly involved in the immune response upon vaccination with modified vaccinia virus Ankara (MVA), a promising live viral vaccine vector. We established CD4+T-cell lines specific for MVA-derived epitopes as tools forin vitroanalysis of MHCII antigen processing and presentation in MVA-infected APCs. We provide evidence that infected APCs are able to directly transfer endogenous viral proteins into the MHCII pathway to efficiently activate CD4+T cells. By using knockout mice and chemical inhibitory compounds, we further elucidated the molecular basis, showing that among the various subcellular pathways investigated, proteasomes and autophagy are key players in the endogenous MHCII presentation during MVA infection. Interestingly, although proteasomal processing plays an important role, neither TAP nor LAMP-2 was found to be involved in the peptide transport. Defining the molecular mechanism of MHCII presentation during MVA infection provides a basis for improving MVA-based vaccination strategies by aiming for enhanced CD4+T-cell activation by directing antigens into the responsible pathways.IMPORTANCEThis work contributes significantly to our understanding of the immunogenic properties of pathogens by deciphering antigen processing pathways contributing to efficient activation of antigen-specific CD4+T cells. We identified autophagosome formation, proteasomal activity, and lysosomal integrity as being crucial for endogenous CD4+T-cell activation. Since poxvirus vectors such as MVA are already used in clinical trials as recombinant vaccines, the data provide important information for the future design of optimized poxviral vaccines for the study of advanced immunotherapy options.

scholarly journals Exogenous peptides compete for the presentation of endogenous antigens to major histocompatibility complex class II-restricted T cells.

1991 ◽  
Vol 174 (4) ◽  
pp. 945-948 ◽  
Author(s):  
L Adorini ◽  
J Moreno ◽  
F Momburg ◽  
G J Hämmerling ◽  
J C Guéry ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Egg White Lysozyme ◽  
Histocompatibility Complex

Antigen-presenting cells (APC) transfected with a construct encoding the hen egg-white lysozyme (HEL) amino acid sequence 1-80 constitutively present HEL peptides complexed to major histocompatibility complex (MHC) class II molecules to specific T cell hybridomas, indicating that endogenous cellular antigens can be efficiently presented to class II-restricted T cells. Here we show that exogenous peptide competitors added to HEL-transfected APC can inhibit the presentation of endogenous HEL peptides to class II-restricted T cells. The inhibition is specific for the class II molecule binding the competitor peptide, and it affects to the same extent presentation of exogenous or endogenous HEL peptides. These results, demonstrating that an exogenous competitor can inhibit class II-restricted T cell activation induced by endogenous as well as exogenous antigen, suggest lack of strict compartmentalization between endogenous and exogenous pathways of antigen presentation. Since autoreactive T cells may recognize endogenous, as well as exogenous antigens, the results have implications for the treatment of autoimmune diseases by MHC blockade.

scholarly journals T cell receptor interaction with peptide/major histocompatibility complex (MHC) and superantigen/MHC ligands is dominated by antigen.

1993 ◽  
Vol 178 (2) ◽  
pp. 713-722 ◽  
Author(s):  
E W Ehrich ◽  
B Devaux ◽  
E P Rock ◽  
J L Jorgensen ◽  
M M Davis ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Amino Acid ◽  
T Cell ◽  
T Cell Activation ◽  
Single Amino Acid ◽  
Receptor Interaction ◽  
Antigenic Peptides ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

While recent evidence strongly suggests that the third complementarity determining regions (CDR3s) of T cell receptors (TCRs) directly contact antigenic peptides bound to major histocompatibility complex (MHC) molecules, the nature of other TCR contact(s) is less clear. Here we probe the extent to which different antigens can affect this interaction by comparing the responses of T cells bearing structurally related TCRs to cytochrome c peptides and staphylococcal enterotoxin A (SEA) presented by 13 mutant antigen-presenting cell (APC) lines. Each APC expresses a class II MHC molecule (I-Ek) with a single substitution of an amino acid residue predicted to be located on the MHC alpha helices and to point "up" towards the TCR. We find that very limited changes (even a single amino acid) in either a CDR3 loop of the TCR or in a contact residue of the antigenic peptide can have a profound effect on relatively distant TCR/MHC interactions. The extent of these effects can be as great as that observed between T cells bearing entirely different TCRs and recognizing different peptides. We also find that superantigen presentation entails a distinct mode of TCR/MHC interaction compared with peptide presentation. These data suggest that TCR/MHC contacts can be made in a variety of ways between the same TCR and MHC, with the final configuration apparently dominated by the antigen. These observations suggest a molecular basis for recent reports in which either peptide analogues or superantigens trigger distinct pathways of T cell activation.

scholarly journals Peptide-Major Histocompatibility Complex Dimensions Control Proximal Kinase-Phosphatase Balance during T Cell Activation

2009 ◽  
Vol 284 (38) ◽  
pp. 26096-26105 ◽  
Author(s):  
Kaushik Choudhuri ◽  
Mathew Parker ◽  
Anita Milicic ◽  
David K. Cole ◽  
Michael K. Shaw ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Complex Dimensions

Involvement of major histocompatibility complex class I antigens in T cell activation

1990 ◽  
Vol 20 (7) ◽  
pp. 1553-1561 ◽  
Author(s):  
Jai Dev Dasgupta ◽  
Eduardo Egea ◽  
Valerie Relias ◽  
Antonio Iglesias ◽  
Paul Gladstone ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Major Histocompatibility Complex Class ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Histocompatibility Complex
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