551: An MHC class II disparity raises the threshold for tolerance induction in pulmonary allografts in miniature swine

The process of antigen recognition depends in part on the amount of peptide antigen available and the affinity of the T cell receptor for a particular peptide-major histocompatibility complex (MHC) molecule complex. The availability of self antigen is limited by antigen processing, which is compartmentalized such that peptide antigens presented by MHC class I molecules originate in the cytoplasm, whereas peptide antigens presented by MHC class II molecules are acquired from the endocytic pathway. This segregation of the antigen-processing pathways may limit the diversity of antigens that influence the development and selection of, e.g., CD4-positive, MHC class II-specific T cells. Selection in this case might involve only a subset of self-encoded proteins, specifically those that are plasma membrane bound or secreted. To study these aspects of immune development, we engineered pigeon cytochrome for expression in transgenic mice in two forms: one in which it was expressed as a type II plasma membrane protein, and a second in which it was targeted to the mitochondria after cytoplasmic synthesis. Experiments with these mice clearly show that tolerance is induced in the thymus, irrespective of antigen compartmentation. Using radiation bone marrow chimeras, we further show that cytoplasmic/mitochondrial antigen gains access to the MHC class II pathway by direct presentation. As a result of studying the anatomy of the thymus, we show that the amount of antigen and the affinity of the TCR affect the location and time point of thymocytes under-going apoptosis.

Download Full-text

Effects of MHC class II antigens on the development of cardiac allograft vasculopathy in miniature swine

The Journal of Heart and Lung Transplantation ◽

10.1016/s1053-2498(99)80079-5 ◽

1999 ◽

Vol 18 (1) ◽

pp. 53

Author(s):

K. Mawulawde ◽

M.R. Pins ◽

M.T. Menard ◽

K. Yamada ◽

J.S. Allan ◽

...

Keyword(s):

Mhc Class Ii ◽

Class Ii ◽

Cardiac Allograft Vasculopathy ◽

Cardiac Allograft ◽

Miniature Swine ◽

Allograft Vasculopathy ◽

Mhc Class Ii Antigens ◽

Class Ii Antigens

Download Full-text

Neonatal tolerance induction in the thymus to MHC-class II-associated antigens IV. Significance of intrathymic chimerism of blood-born la+ cells in Mls tolerance

Cellular Immunology ◽

10.1016/0008-8749(91)90360-n ◽

1991 ◽

Vol 136 (2) ◽

pp. 373-387 ◽

Cited By ~ 8

Author(s):

Masamichi Hosono ◽

Mafumi Kurozumi ◽

Muneo Inaba ◽

Shin Ideyama ◽

Mitsuru Tomana ◽

...

Keyword(s):

Mhc Class Ii ◽

Tolerance Induction ◽

Class Ii

Download Full-text

Ex Vivo Blockade of NF-[dappa]B Signaling in Alloreactive T Cells Prevents Murine Graft-Versus-Host Disease (GVHD).

Blood ◽

10.1182/blood.v104.11.3058.3058 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3058-3058

Author(s):

Matthew J. O’Shaughnessy ◽

Christine Vogtenhuber ◽

Jonathon S. Serody ◽

Raquel Sitcheran ◽

Albert S. Baldwin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Ex Vivo ◽

Tolerance Induction ◽

Class Ii ◽

Maximal Effect ◽

Alloreactive T Cells ◽

Iκb Kinase

Abstract A failure of IL-2 transcription has been associated with tolerance induction. We hypothesized that inhibition of the NF-κB pathway in alloreactive T-cells, which is critical for IL-2 transcription, could lead to alloantigen-specific hyporesponsiveness and prevention of GVHD. PS1145, a potent inhibitor of IκB kinase, and hence NF-κB activation, was added to an MLR culture consisting of CD4+ T-cells and MHC class II-disparate stimulators. Inhibition of NF-κB activity was verified by EMSA and confocal microscopy. Global inhibition of cytokine production and T-cell hyporesponsiveness was observed which persisted after washing T-cells and re-exposure to alloantigen. Responses to non-specific mitogens remained largely intact and alloantigen hyporesponsiveness was reversed by exogenous IL-2. Treatment of T cells and stimulator cells with PS1145 was required for maximal effect. Depletion of CD4+CD25+ cells from the MLR indicated that these cells were not required for tolerance induction in this system. Using an MLR system containing alloreactive and non-alloreactive transgenic T cells indicated that PS1145 treatment increased the rate of T-cell apoptosis selectively in alloreactive cells. Data from each of 4 experiments showed that GVHD in recipients of ex vivo PS1145 treated cells was profoundly inhibited, whereas CD4+ T-cells recovered from a vehicle-treated 7-day MLR were uniformly fatal upon adoptive transfer into sublethally irradiated MHC class II-disparate recipients. Studies addressing non-alloreactive in vivo responses of PS1145 treated T cells will also be presented. Our studies indicate that the NF-κB pathway is a critical regulator of productive alloresponses and provide a novel ex vivo approach to induce alloantigen-specific tolerance as a means of preventing GVHD.

Download Full-text

Retroviral vectors transfer functional MHC class II heterodimers into bone marrow: A genetic approach to tolerance induction

Transplantation Proceedings ◽

10.1016/s0041-1345(96)00463-0 ◽

1997 ◽

Vol 29 (1-2) ◽

pp. 1129 ◽

Cited By ~ 4

Author(s):

S. Germana ◽

H. Shimada ◽

D.H. Sachs ◽

C. LeGuern

Keyword(s):

Bone Marrow ◽

Mhc Class Ii ◽

Tolerance Induction ◽

Class Ii ◽

Retroviral Vectors ◽

Genetic Approach

Download Full-text

Presentation of a self-peptide for in vivo tolerance induction of CD4+ T cells is governed by a processing factor that maps to the class II region of the major histocompatibility complex locus.

Journal of Experimental Medicine ◽

10.1084/jem.182.5.1481 ◽

1995 ◽

Vol 182 (5) ◽

pp. 1481-1491 ◽

Cited By ~ 13

Author(s):

E V Fedoseyeva ◽

R C Tam ◽

P L Orr ◽

M R Garovoy ◽

G Benichou

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

Tolerance Induction ◽

Class Ii ◽

The Self ◽

T Cell Repertoire ◽

Cell Repertoire ◽

Mhc Class Ii Molecules ◽

Self Peptides

Self-proteins are regularly processed for presentation to autoreactive T cells in association with both class I and class II major histocompatibility complex (MHC) molecules. The presentation of self-peptides plays a crucial role in the acquisition of T cell repertoire during thymic selection. We previously reported that the self-MHC class I peptide Ld 61-80 was immunogenic in syngeneic B10.A mice (H-2a). We showed that despite its high affinity for self-MHC class II molecules, Ld 61-80 peptide failed to induce elimination of autoreactive CD4+ T cells, presumably due to incomplete processing and presentation in the B10.A's developing thymus (cryptic-self peptide). In this report, we showed that the cryptic phenotype was not an intrinsic property of the self-peptide Ld 61-80 since it was found to be naturally presented and subsequently tolerogenic in BALB/c mice (H-2d) (dominant self-peptide). In addition, the self-peptide Ld 61-80 was found to be immunogenic in different H-2a mice while it was invariably tolerogenic in H-2d mice regardless of their background genes. We observed that Ld 61-80 bound equally well to H-2d and H-2k MHC class II molecules. Also, no correlation was found between the quantity of self-Ld protein and the tolerogenicity of Ld 61-80. Surprisingly, Ld 61-80 was not naturally presented in (H-2d x H-2a) F1 mice, indicating that the H-2a MHC locus contained a gene that impaired the presentation of the self-peptide. Analyses of T cell responses to the self-peptide in several H-2 recombinant mice revealed that the presentation of Ld 61-80 was controlled by genes that mapped to a 170-kb portion of the MHC class II region. This study shows that (a) endogenously processed self-peptides presented by MHC class II molecules are involved in shaping the CD4+ T cell repertoire in the thymus; (b) The selection of self-peptides for presentation by MHC class II molecules to nascent autoreactive T cells is influenced by nonstructural MHC genes that map to a 170-kb portion of the MHC class II region; and (c) the MHC locus of H-2a mice encodes factors that prevent or abrogate the presentation by MHC class II molecules of the self-peptide Ld 61-80. These findings may have important implications for understanding the molecular mechanisms involved in T cell repertoire acquisition and self-tolerance induction.

Download Full-text