Cytotoxic T cell recognition of an endogenous class I HLA peptide presented by a class II HLA molecule.

Abstract

SummaryHuman leukocytes were stimulated in vitro with peptides corresponding in sequence to the highly variable helix of the a1 domain of various HLA-B and -C molecules. A CD4'CD8 -cytotoxic T cell line, CTLAV, that is specific for the HLA-B7 peptide presented by HLA-DR11 .1 was obtained. The HLA-DR11.2 molecule, which only differs at three residues from HLA-DR11 .1, did not present the HLA-B7 peptide to CTLAV Peptides from the a1 domain helix of other HLA-A and HLA-B molecules, but not HLA-C molecules, competed with the HLA-B7 peptide for binding to HLA-DR11.1. A cell line (WT50) that coexpresses HLA-B7 and HLA-DR11 .1 was killed by CTLAV in the absence ofany added HLAB7 peptide. The processing and presentation ofHLAB7 in these cells appears to be through the endogenous, and not the exogenous, pathway of antigen presentation. Thus, Brefeldin A inhibits presentation and chloroquine does not . Furthermore, introduction of purified HLA-B7 molecules into HLA-DR11 .1', HLA-B7 -cells by cytoplasmic loading via osmotic lysis of pinosomes, but not by simple incubation, rendered them susceptible to CTLAV killing. These results provide an example of class II major histocompatibility complex (MHC) presentation of a constitutively synthesized self protein that uses the endogenous pathway ofantigen presentation . They also emphasize the capacity for presentation of MHC peptides by MHC molecules.

The human alloreactive CD4+ T-cell repertoire is biased to a Th17 response and the frequency is inversely related to the number of HLA class II mismatches

“…The mechanism of action may be by either the direct or indirect allogeneic antigen presentation pathway. [1][2][3][4] For instance, immunization with allogeneic HLA peptides presented by acceptor HLA class II significantly increases both acute and chronic rejection after organ transplantation. 5 In addition, CD4 ϩ T-cell help is necessary to facilitate full differentiation of graft-infiltrating CD8 ϩ T cells.…”

Transfer of the inflammatory disease of HLA-B27 transgenic rats by bone marrow engraftment.

“…B27 transgenic rats can mount strong B27-restricted CTL responses (37), but it is not yet known whether this is the predominant effector mechanism in either the spontaneous or transferred disease. Presentation of a B27-derived peptide (38,39) by rat MHC molecules is another potential disease mechanism that has not yet been excluded. Further experiments should help identify the role ofT cells, the specific BM-derived populations responsible for the transferred disease, and the molecular role of B27, as well as whether recognition of an exogenous antigen (31) or a self-antigen (40) is involved.…”

Peptide-mediated allo-recognition of HLA-B27 by cytotoxic T lymphocytes

“…Constitutive peptide binding appears to be also necessary for stability of the class-I antigens expressed at the cell surface (Ljunggren et al, 1990). Third, some allo-reactive T-cells can recognize a peptide in the context of the target allo-antigen (Song et Olson et al, 1989;Heath et al, 1989;de Koster et al, 1989;Essaket et al, 1990;Schendel, 1990;Chen et al, 1990). The nature, multiplicity and relative proportions of the endogenous peptides bound to any given class-I molecule is unknown, although MHC-derived peptides are presented by intact MHC molecules in some cases.…”