Antagonism of Antiviral and Allogeneic Activity of a Human Public CTL Clonotype by a Single Altered Peptide Ligand: Implications for Allograft Rejection

Abstract

Alloreactive T lymphocytes are central mediators of graft-versus-host disease and allograft rejection. A public CTL clonotype with specificity for the alloantigens HLA-B*4402 and B*4405 is often expanded to large numbers in healthy HLA-B*0801+ individuals, driven by cross-reactive stimulation with the common, persistent herpesvirus EBV. Since such alloreactive memory CTL expansions have the potential to influence transplantation outcome, altered peptide ligands (APLs) of the target HLA-B*0801-binding EBV peptide, FLRGRAYGL, were screened as specific antagonists for this immunodominant clonotype. One APL, FLRGRFYGL, exerted powerful antagonism of a prototypic T cell clone expressing this immunodominant TCR when costimulated with target cells presenting HLA-B*0801FLRGRAYGL. Significantly, this APL also reduced the lysis of allogeneic target cells expressing HLA-B*4402 by up to 99%. The affinities of the agonist and antagonist complexes for the public TCR, measured using solution and solid-phase assays, were 8 and 138 μM, respectively. Surprisingly, the half-life of the agonist and antagonist complexes was similar, yet the association rate for the antagonist complex was significantly slower. These observations were further supported by structural studies that suggested a large conformational hurdle was required to ligate the immunodominant TCR to the HLA-B*0801 antagonist complex. By defining an antagonist APL against an immunodominant alloreactive TCR, these findings raise the prospect of exploiting such peptides to inhibit clinical alloreactivity, particularly against clonal T cell expansions that react with alloantigens.

Fast on-rates allow short dwell time ligands to activate T cells

“…In contrast to the canonical t 1/2 models, most T-cell activation studies suggesting that K D is a better predictor of ligand potency have k on larger than or close to the rebinding threshold (5,6). Our data suggest that these correlations with K D occur because …”

“…Although ligand potency could be dependent on each of these binding characteristics, research over the past two decades has suggested that only the K D or t 1/2 matters. Mechanistically, these two mutually exclusive models have been interpreted to mean that T cells are either (i) sensitive to the number of TCRs simultaneously bound to pMHC (3)(4)(5)(6) or (ii) sensitive to ligands that produce a long enough interaction to phosphorylate the TCR complex fully (8-11, 13). In seeming contradiction to both theories, data presented here suggest that neither the K D nor t 1/2 determines the potency of T-cell ligands.…”

Patients, Pathogens, and Protective Immunity: The Relevance of Virus-Induced Alloreactivity in Transplantation

“…Further analysis has confirmed that the anti-EBV response is sufficiently broad to accommodate the specific loss of the allocross-reactive subset while maintaining viral control (46). This suggests that approaches such as those developed by Burrows et al (49,50) describing the use an altered peptide ligand to an EBV epitope have the potential to antagonize the allospecific response without incapacitating EBV control.…”

The Role of Production Frequency in the Sharing of Simian Immunodeficiency Virus-Specific CD8+ TCRs between Macaques

“…53), monkeys (38), rodents (39 -50, 54), and rainbow trout (51). The sharing of TCRs between individuals has also been observed in a variety of immune responses, including both acute (8,12,33,45,46,48) and persistent infections (10, 14, 15, 19 -21, 25-27, 29, 30, 32, 34 -38), autoimmune diseases (9, 11, 13, 16 -18, 22-24, 49, 50, 54), alloreactive states (28,31,42,43), and tumor rejection (41). Moreover, studies have suggested that public TCRs may play specific roles in many immune responses.…”