scholarly journals Major histocompatibility complex class II-associated peptides control the presentation of bacterial superantigens to T cells.

1996 ◽  
Vol 183 (3) ◽  
pp. 1083-1092 ◽  
Author(s):  
R Wen ◽  
G A Cole ◽  
S Surman ◽  
M A Blackman ◽  
D L Woodland
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Bacterial Superantigens ◽  
Toxic Shock Syndrome Toxin

Recent studies have shown that only a subset of major histocompatibility complex (MHC) class II molecules are able to present bacterial superantigens to T cells, leading to the suggestion that class-II associated peptides may influence superantigen presentation. Here, we have assessed the potential role of peptides on superantigen presentation by (a) analyzing the ability of superantigens to block peptide-specific T cell responses and (b) analyzing the ability of individual peptides to promote superantigen presentation on I-Ab-expressing T2 cells that have a quantitative defect in antigen processing. A series of peptides is described that specifically promote either toxic shock syndrome toxin (TSST) 1 or staphylococcal enterotoxin A (SEA) presentation. Whereas some peptides promoted the presentation of TSST-1 (almost 5,000-fold in the case of one peptide), other peptides promoted the presentation of SEA. These data demonstrate that MHC class II-associated peptides differentially influence the presentation of bacterial superantigens to T cells.

scholarly journals Major histocompatibility complex-restricted recognition of retroviral superantigens by V beta 17+ T cells.

1992 ◽  
Vol 176 (1) ◽  
pp. 275-280 ◽  
Author(s):  
M A Blackman ◽  
F E Lund ◽  
S Surman ◽  
R B Corley ◽  
D L Woodland
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Direct Role ◽  
Histocompatibility Complex ◽  
Class Ii Mhc ◽  
Mhc Class Ii Molecules

It has been established that at least some V beta 17+ T cells interact with an endogenous superantigen encoded by the murine retrovirus, Mtv-9. To analyze the role of major histocompatibility complex (MHC) class II molecules in presenting the Mtv-9 encoded superantigen, vSAG-9 to V beta 17+ hybridomas, a panel of nine hybridomas was tested for their ability to respond to A20/2J (H-2d) and LBK (H-2a) cells which had been transfected with the vSAG-9 gene. Whereas some of the hybridomas recognized vSAG-9 exclusively in the context of H-2a, other hybridomas recognized vSAG-9 exclusively in the context of H-2d or in the context of both H-2d and H-2a. These results suggest that: (a) the class II MHC molecule plays a direct role in the recognition of retroviral superantigen by T cells, rather than serving simply as a platform for presentation; and, (b) it is likely that components of the TCR other than V beta are involved in the vSAG-9/TCR/class II interaction.

scholarly journals Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice.

1994 ◽  
Vol 179 (4) ◽  
pp. 1137-1143 ◽  
Author(s):  
A M Jevnikar ◽  
M J Grusby ◽  
L H Glimcher
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
De Novo ◽  
Class Ii ◽  
Systemic Lupus Erythematosis ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Histocompatibility Complex

MRL-lpr mice develop aggressive autoimmune kidney disease associated with increased or de novo renal expression of major histocompatibility complex (MHC) class II molecules and a massive systemic expansion of CD4-CD- double negative (DN) T cells. Whereas non-MHC linked genes can have a profound effect on the development of nephritis, lymphadenopathy, and anti-DNA antibody production in MRL-lpr mice, the role of MHC molecules has not been unequivocally established. To study the role of MHC class II in this murine model of systemic lupus erythematosis, class II-deficient MRL-lpr mice (MRL-lpr -/-) were created. MRL-lpr -/- mice developed lymphadenopathy but not autoimmune renal disease or autoantibodies. This study demonstrates that class II expression is critical for the development of autoaggressive CD4+ T cells involved in autoimmune nephritis and clearly dissociates DN T cell expansion from autoimmune disease initiation.

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 Invariant chain and DM edit self-peptide presentation by major histocompatibility complex (MHC) class II molecules.

1996 ◽  
Vol 184 (5) ◽  
pp. 1747-1753 ◽  
Author(s):  
J F Katz ◽  
C Stebbins ◽  
E Appella ◽  
A J Sant
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Binding Pocket ◽  
Surface Expression ◽  
Class Ii ◽  
Invariant Chain ◽  
Generalized Function ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

We have studied the consequences of invariant chain (Ii) and DM expression on major histocompatibility complex (MHC) class II function. Ii has a number of discrete functions in the biology of class II, including competitive blocking of peptide binding in the endoplasmic reticulum and enhancing localization in the endocytic compartments. DM is thought to act primarily in endosomes to promote dissociation of the Ii-derived (CLIP) peptide from the class II antigen-binding pocket and subsequent peptide loading. In this study, we have evaluated the functional role of Ii and DM by examining their impact on surface expression of epitopes recognized by a large panel of alloreactive T cells. We find most epitopes studied are influenced by both Ii and DM. Most strikingly, we find that surface expression of a significant fraction of peptide-class II complexes is extinguished, rather than enhanced, by DM expression within the APC. The epitopes antagonized by DM do not appear to be specific for CLIP. Finally, we found that DM was also able to extinguish recognition of a defined peptide derived from the internally synthesized H-2Ld protein. Thus, rather than primarily serving in the removal of CLIP, DM may have a more generalized function of editing the array of peptides that are presented by class II. This editing can be either positive or negative, suggesting that DM plays a specifying role in the display of peptides presented to CD4 T cells.

scholarly journals Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice.

1993 ◽  
Vol 178 (2) ◽  
pp. 589-596 ◽  
Author(s):  
T M Laufer ◽  
M G von Herrath ◽  
M J Grusby ◽  
M B Oldstone ◽  
L H Glimcher
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Islet Cells ◽  
Autoimmune Diabetes ◽  
Class Ii ◽  
Dependent Diabetes Mellitus ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease marked by hyperglycemia and mononuclear cell infiltration of insulin-producing beta islet cells. Predisposition to IDDM in humans has been linked to the class II major histocompatibility complex (MHC), and islet cells often become aberrantly class II positive during the course of the disease. We have used two recently described transgenic lines to investigate the role of class II molecules and CD4+ T cells in the onset of autoimmune insulitis. Mice that are class II deficient secondary to a targeted disruption of the A beta b gene were bred to mice carrying a transgene for the lymphocytic choriomenigitis virus (LCMV) glycoprotein (GP) targeted to the endocrine pancreas. Our results indicate that class II-deficient animals with and without the GP transgene produce a normal cytotoxic T lymphocyte response to whole LCMV. After infection with LCMV, GP-transgenic class II-deficient animals develop hyperglycemia as rapidly as their class II-positive littermates. Histologic examination of tissue sections from GP-transgenic class II-deficient animals reveals lymphocytic infiltrates of the pancreatic islets that are distinguishable from those of their class II-positive littermates only by the absence of infiltrating CD4+ T cells. These results suggest that in this model of autoimmune diabetes, CD4+ T cells and MHC class II molecules are not required for the development of disease.

scholarly journals Altered major histocompatibility complex restriction in the NK1.1+Ly-6Chi autoreactive CD4+ T cell subset from class II-deficient mice.

1994 ◽  
Vol 180 (6) ◽  
pp. 2419-2424 ◽  
Author(s):  
I Kariv ◽  
R R Hardy ◽  
K Hayakawa
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Cell Subset ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Selective Enrichment ◽  
Histocompatibility Complex ◽  
Heat Stable Antigen ◽  
Autoreactive Cells

We previously demonstrated selective enrichment of major histocompatibility complex (MHC) class II-specific autoreactive T cells in a subset of mouse CD4+ thymocytes. Here we show that a significant fraction of these autoreactive cells in the normal adult thymus expresses NK1.1 and high levels of Ly-6C and also exhibits flexibility in MHC restriction. In normal mice, this NK1.1+Ly-6Chi subfraction accounts for 10-50% of the CD4+ autoreactive subset and is enriched for MHC class II-restricted autoreactive cells as determined by mixed leukocyte reaction frequency analysis, similar to NK1.1-Ly-6C-CD4+ autoreactive cells. In contrast, in the thymus of class II-deficient littermate mice, NK1.1+Ly-6Chi cells account for most of the mature heat stable antigen (HSA)-CD4+ fraction and exhibit MHC-restricted non-class II autoreactivity. Thus, NK1.1+Ly-6ChiCD4+ T cells show flexibility in MHC class restriction, but their autoreactivity remains MHC dependent.

scholarly journals Binding sites for bacterial and endogenous retroviral superantigens can be dissociated on major histocompatibility complex class II molecules.

1994 ◽  
Vol 179 (3) ◽  
pp. 1029-1034 ◽  
Author(s):  
J Thibodeau ◽  
N Labrecque ◽  
F Denis ◽  
B T Huber ◽  
R P Sékaly
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Binding Sites ◽  
Cell Receptor ◽  
Class Ii ◽  
Bacterial Toxins ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Molecules

Bacterial and retroviral superantigens (SAGs) interact with major histocompatibility complex (MHC) class II molecules and stimulate T cells upon binding to the V beta portion of the T cell receptor. Whereas both types of molecules exert similar effects on T cells, they have very different primary structures. Amino acids critical for the binding of bacterial toxins to class II molecules have been identified but little is known of the molecular interactions between class II and retroviral SAGs. To determine whether both types of superantigens interact with the same regions of MHC class II molecules, we have generated mutant HLA-DR molecules which have lost the capacity to bind three bacterial toxins (Staphylococcus aureus enterotoxin A [SEA], S. aureus enterotoxin B [SEB], and toxic shock syndrome toxin 1 [TSST-1]). Cells expressing these mutated class II molecules efficiently presented two retroviral SAGs (Mtv-9 and Mtv-7) to T cells while they were unable to present the bacterial SAGs. These results demonstrate that the binding sites for both types of SAGs can be dissociated.

scholarly journals Analysis of the Role of  Variation of Major Histocompatibility Complex Class II Expression on Nonobese Diabetic (NOD) Peripheral T Cell Response

1998 ◽  
Vol 188 (12) ◽  
pp. 2267-2275 ◽  
Author(s):  
William M. Ridgway ◽  
Hiroaki Ito ◽  
Marcella Fassò ◽  
Chen Yu ◽  
C. Garrison Fathman
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Transgenic Mice ◽  
Mhc Class Ii ◽  
Nod Mice ◽  
Class Ii ◽  
Nonobese Diabetic ◽  
Histocompatibility Complex

The current paradigm of major histocompatibility complex (MHC) and disease association suggests that efficient binding of autoantigens by disease-associated MHC molecules leads to a T cell–mediated immune response and resultant autoimmune sequelae. The data presented below offer a different model for this association of MHC with autoimmune diabetes. We used several mouse lines expressing different levels of I-Ag7 and I-Ak on the nonobese diabetic (NOD) background to evaluate the role of MHC class II in the previously described NOD T cell autoproliferation. The ratio of I-Ag7 to I-Ak expression correlated with the peripheral T cell autoproliferative phenotype in the mice studied. T cells from the NOD, [NOD × NOD.I-Anull]F1, and NOD I-Ak transgenic mice demonstrated autoproliferative responses (after priming with self-peptides), whereas the NOD.H2h4 (containing I-Ak) congenic and [NOD × NOD.H2h4 congenic]F1 mice did not. Analysis of CD4+ NOD I-Ak transgenic primed lymph node cells showed that autoreactive CD4+ T cells in the NOD I-Ak transgenic mice were restricted exclusively by I-Ag7. Considered in the context of the avidity theory of T cell activation and selection, the reported poor peptide binding capacity of NOD I-Ag7 suggested a new hypothesis to explain the effects of MHC class II expression on the peripheral autoimmune repertoire in NOD mice. This new explanation suggests that the association of MHC with diabetes results from “altered” thymic selection in which high affinity self-reactive (potentially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression in NOD mice (and in humans) in susceptibility to insulin-dependent diabetes mellitus.

scholarly journals Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease.

1993 ◽  
Vol 178 (5) ◽  
pp. 1675-1680 ◽  
Author(s):  
H Deng ◽  
R Apple ◽  
M Clare-Salzler ◽  
S Trembleau ◽  
D Mathis ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Class Ii ◽  
Dependent Diabetes Mellitus ◽  
Protective Effects ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

How peptide-major histocompatibility complex (MHC) class II complexes are naturally generated is still unknown, but accumulating evidence suggests that unfolding proteins or long peptides can become bound to class II molecules at the dominant determinant before proteolytic cleavage. We have compared the immunogenicity of hen egg-white lysozyme (HEL) in nonobese diabetic (NOD), (NOD x BALB/c)F1, and E(d) alpha transgenic NOD mice. We find that a response to the subdominant ANOD-restricted determinant disappears upon introduction of an E(d) molecule, and is restored when scission of HEL separates this determinant from its adjoining, competitively dominant, E(d)-restricted determinant. This suggests that the E(d) molecule binds and protects its dominant determinant on a long peptide while captured neighboring determinants are lost during proteolysis. These results provide clear evidence for "determinant capture" as a mechanism of determinant selection during antigen processing and a possible explanation for MHC-protective effects in insulin-dependent diabetes mellitus.

Sign in / Sign up

Export Citation Format

Share Document