High-Frequency Alloreactive T Cells Augment Effector Function of Low-Frequency CD8+ T-Cell Responses Under CD28/CD154 Blockade

Abstract

Background Blockade of costimulatory molecules is a potent method of inducing long-term graft survival. We have previously addressed the issue of donor-reactive T cell precursor frequency on relative costimulation dependence, and found that the presence of a high precursor frequency of donor-reactive CD8+ T cells resulted in costimulation blockade-resistant graft rejection, whereas the presence of a low-frequency donor-reactive population did not. To address the mechanisms by which high frequency T cells obviated the requirement for costimulation, we asked whether a low frequency population responding concomitantly with a high frequency response also demonstrated costimulation independence. Methods A model system was established in which B6 mice containing a low frequency of anti-mOVA responders and a high frequency of anti-BALB/c responders received a skin graft from B6.mOVAxBALB/c F1 donors in the presence or absence of CTLA-4 Ig/anti-CD154 costimulatory blockade. Results Results revealed that in the presence of costimulation blockade, high frequency anti-BALB/c T cells augmented the effector activity of low frequency anti-mOVA T cells, but did not enhance the accumulation of anti-mOVA T cells capable of mediating graft rejection. Conclusions These results demonstrate that both antigen-specific and antigen-independent factors contribute to the relative costimulation-independence of high frequency T cell responses.

Alloimmunity But Not Viral Immunity Promotes Allograft Loss in a Mouse Model of Polyomavirus-Associated Allograft Injury

“…40 To better control for variables in the transferred cell population, we performed adoptive transfer experiments using a well-characterized surrogate minor antigen transplant model system that uses tissue obtained from mice that express chicken OVA and OVA-specific OT-I T cell receptor-transgenic CD8 + T cells. 41 In 1 set of experiments, donor kidneys were harvested from mice genetically engineered to express membrane-bound OVA (mOVA) under the β-actin promoter such that it is expressed on the surface of all tissues including the transplanted kidney. In this group of experiments, the transferred OT-I T cells were effectively antidonor T cells.…”

Update on CD40 and CD154 Blockade in Transplant Models

“…The presence of high initial CD4 + or CD8 + donor-reactive T-cell precursor frequency might render the transplant recipients resistant to costimulation blockade [85–87]. These discoveries might have important clinical implication as the influence of alloreactive T-cell precursors could be minimized or eliminated through the selection of donor-recipient combinations with low pretransplant donor-reactive CD4 + and CD8 + T cell frequencies [77].…”

T Cell Costimulation Blockade and Organ Transplantation: A Change of Philosophy for Transplant Immunologists?

“…Or has thinking shifted to a paradigm in which novel agents that induce graft acceptance experimentally are developed to replace one of the several immune suppressants that are currently administered to organ transplant recipients, with the hope of reducing patient morbidity after transplantation? Many experimental transplant immunologists still employ the original costimulatory blocking agents reported by Larsen and colleagues to investigate pathways of experimental transplant tolerance, in keeping with the philosophy initiated by Medawar (15)(16)(17)(18)(19). The study by Larsen and colleagues prompted a different philosophy of how to translate experimental immunological studies into use in patients who require chronic immune modulation.…”