Cross‐reactive memory T cells for Epstein‐Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major histocompatibility complex‐bound peptide by T cells and its role in alloreactivity

Abstract

In the present report, cytotoxic T lymphocyte (CTL) clones are described that display dual specificity for one of two common human leukocyte antigens (HLA B14 or B35) as alloantigens, and an immunodominant epitope (FLRGRAYGL) from Epstein-Barr virus (EBV) that binds to HLA B8. These T cell clonotypes were isolated from several unrelated HLA B8+, EBV-exposed individuals, and each distinct cross-reactivity pattern was associated with a common, public T cell receptor (TCR). In some individuals, CTL cross-reactive with these alloantigens completely dominated the memory response to this EBV epitope. Moreover, these memory T cells to EBV could be reactivated as a significant component of the repertoire of CTL responding to allogeneic stimulator cells expressing either HLA B14 or B35. These data illustrate how a history of infection with an immunogenic virus such as EBV can augment responsiveness to particular alloantigens; such influences may underlie the observed clinical association between herpesvirus infection and both allograft rejection and graft-versus-host disease. We have also explored the molecular basis for T cell cross-reactivity with alloantigens using the HLA B35 allo-reactive CTL clonotype. To elucidate the structural features of peptides that may be cross-recognized by these T cells, mono-substituted analogs of the viral epitope were screened for recognition, revealing broad specificity for major histocompatibility complex (MHC)-bound peptide. Based on the particular amino acid changes tolerated by the CTL at each peptide position, the human protein sequence database was searched for possible sequences that were recognized in association with HLA B35. Four peptides were identified (MPEATVYGL, IPIAPVYGM, KPSPPYFGL, and KPIVVLHGY) that were powerful activating ligands for the CTL when presented on HLA B35 but not B8. Thus, equivalent epitopes, capable of fully activating a single TCR, were formed by peptides with minimal obvious sequence homology bound to either HLA B8 or B35. These data indicate that degenerate peptide recognition by TCR may play an important role in the vigorous response of self-MHC-restricted T cells to alloantigens.

A Human CTL Recognizes a Caspase-8-Derived Peptide on Autologous HLA-B*3503 Molecules and Two Unrelated Peptides on Allogeneic HLA-B*3501 Molecules

“…This clone was also stimulated by HLA-B35 cells. Burrows and colleagues tested analogues of the viral peptides to identify the amino acid changes tolerated by the CTL (7). This information, in combination with a peptide binding motif for HLA-B35, was used to search a human protein sequence database.…”

Induction of long‐lasting multi‐specific CD8+ T cells by a four‐component DNA‐MVA/HIVA‐RENTA candidate HIV‐1 vaccine in rhesus macaques

“…The extent of CD8 + T cell cross-reactivity remains controversial with evidence both for [10][11][12][13][14][15][16][17] and against [18][19][20][21][22] its broad effectiveness. At least in the one animal tested on two occasions, we observed cross-reactivity of CD8 + T cells with 50% of tested epitope variants not present in the vaccine (Fig.…”

“…A number of studies have addressed this point with mixed results. While some studies clearly detected cross-clade-reactive HIV-1-specific CD8 + T cell responses [10][11][12][13][14][15][16][17], there is substantial evidence that CD8 + T cells can be highly sequence-specific [18][19][20][21][22]. This was best demonstrated in systematic studies employing all possible single amino acid substitutions in each position of an MHC class I epitope, which suggested that as few as one in three epitope variants was recognized by a given T cell receptor [18,23].…”

Cross-immune tolerance: conception and its potential significance on transplantation tolerance

“…There is compelling evidence to suggest that the crossreactive T cells also contribute significantly to the alloreactive repertoire in humans. One of the typical examples in this regard is the finding that human T-cell clones specific for the Epstein-Barr virus peptide presented by human leukocyte antigen-B8 also respond to three common allogeneic human leukocyte antigen molecules (B14, B35 or B44), 41,42 suggesting that such Epstein-Barr virus-responsive T cells are potentially alloreactive. Indeed, a strong correlation between virus infections (e.g., Sendai virus, cytomegalovirus or Epstein-Barr virus) and acute allograft rejection has been reported in humans.…”

“…Indeed, a strong correlation between virus infections (e.g., Sendai virus, cytomegalovirus or Epstein-Barr virus) and acute allograft rejection has been reported in humans. 4,41,[43][44][45] It is important to emphasize that certain memory T cells that are programmed to respond to conventional pathogens can also be alloreactive in transplant models, thus contributing significantly to the alloreactive T-cell pool, especially in primate models and humans. 9 Such alloreactive memory T cells may have developed by crossreaction after viral or other pathogen infections, or by other mechanisms like homeostatic proliferation and heterologous immunity.…”