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Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation.

ABSTRACT: Natural killer (NK) cells are a population of innate type I lymphoid cells essential for early anti-viral responses and are known to modulate the course of humoral and cellular-mediated T cell responses. We assessed the role of NK cells in allogeneic CD8 T cell-mediated responses in an immunocompetent mouse model across an MHC class I histocompatibility barrier to determine its impact in therapeutic clinical interventions with polyclonal or monoclonal antibodies (mAbs) targeting lymphoid cells in transplantation. The administration of an NK cell depleting antibody to either CD8 T cell replete or CD8 T cell-depleted naïve C57BL/6 immunocompetent mice accelerated graft rejection. This accelerated rejection response was associated with an in vivo increased cytotoxic activity of CD8 T cells against bm1 allogeneic hematopoietic cells and bm1 skin allografts. These findings show that NK cells were implicated in the control host anti-donor cytotoxic responses, likely by competing for common cell growth factors in both CD8 T cell replete and CD8 T cell-depleted mice, the latter reconstituting in response to lymphopenia. Our data calls for precaution in solid organ transplantation under tolerogenic protocols involving extensive depletion of lymphocytes. These pharmacological biologics with depleting properties over NK cells may accelerate graft rejection and promote aggressive CD8 T cell cytotoxic alloresponses refractory to current immunosuppression.

SUBMITTER: Rodriguez-Barbosa JI

PROVIDER: S-EPMC6204794 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation.

Rodriguez-Barbosa J I JI Ferreras M C MC Buhler L L Jones N D ND Schneider P P Perez-Simon J A JA Perez-Simon J A JA Del Rio M L ML

mAbs 20180905 7

Natural killer (NK) cells are a population of innate type I lymphoid cells essential for early anti-viral responses and are known to modulate the course of humoral and cellular-mediated T cell responses. We assessed the role of NK cells in allogeneic CD8 T cell-mediated responses in an immunocompetent mouse model across an MHC class I histocompatibility barrier to determine its impact in therapeutic clinical interventions with polyclonal or monoclonal antibodies (mAbs) targeting lymphoid cells i ...[more]

PMID: 30036156

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Project description:Reactivation of latent cytomegalovirus (CMV) poses a clinical problem in transiently immunocompromised recipients of hematopoietic cell (HC) transplantation (HCT) by viral histopathology that results in multiple organ manifestations. Compared to autologous HCT and to syngeneic HCT performed with identical twins as HC donor and recipient, lethal outcome of CMV infection is more frequent in allogeneic HCT with MHC/HLA or minor histocompatibility loci mismatch between donor and recipient. It is an open question if a graft-vs.-host (GvH) reaction exacerbates CMV disease, or if CMV exacerbates GvH disease (GvHD), or if interference is mutual. Here we have used a mouse model of experimental HCT and murine CMV (mCMV) infection with an MHC class-I mismatch by gene deletion, so that either HCT donor or recipient lack a single MHC class-I molecule, specifically H-2 Ld. This particular immunogenetic disparity has the additional advantage that it allows to experimentally separate GvH reaction of donor-derived T cells against recipient's tissues from host-vs.-graft (HvG) reaction of residual recipient-derived T cells against the transplanted HC and their progeny. While in HvG-HCT with Ld-plus donors and Ld-minus recipients almost all infected recipients were found to control the infection and survived, almost all infected recipients died of uncontrolled virus replication and consequent multiple-organ viral histopathology in case of GvH-HCT with Ld-minus donors and Ld-plus recipients. Unexpectedly, although anti-Ld-reactive CD8+ T cells were detected, mortality was not found to be associated with GvHD histopathology. By comparing HvG-HCT and GvH-HCT, investigation into the mechanism revealed an inefficient reconstitution of antiviral high-avidity CD8+ T cells, associated with lack of formation of protective nodular inflammatory foci (NIF) in host tissue, selectively in GvH-HCT. Most notably, mice infected with an immune evasion gene deletion mutant of mCMV survived under otherwise identical GvH-HCT conditions. Survival was associated with enhanced antigen presentation and formation of protective NIF by antiviral CD8+ T cells that control the infection and prevent viral histopathology. This is an impressive example of lethal viral disease in HCT recipients based on a failure of the immune control of CMV infection due to viral immune evasion in concert with an MHC class-I mismatch.

Dataset Information

Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation.

Publications

Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation.

Similar Datasets

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